Pyrazolopyrimidine Derivatives or Pharmaceutically Acceptable Salts Thereof

ABSTRACT

A pyrazolopyrimidine derivative represented by formula (1) and pharmaceutically acceptable salt thereof exhibit excellent inhibitory activity against MAPKAP-K2. Accordingly, medicines containing this compound as an active ingredient are expected to be effective for treating diseases mediated by MAPKAP-K2 such as, for example, inflammatory disorder, autoimmune diseases, destructive osteopathy, cancer and/or tumor growth.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of application Ser. No. 11/377,363 filed Mar. 17, 2006, which claims benefit of Provisional Application No. 60/663,205 filed Mar. 21, 2005. The entire disclosures of the prior applications, application Ser. Nos. 11/377,363 and 60/663,205 are considered part of the disclosure of the accompanying divisional application and are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a novel pyrazolopyrimidine derivative or a medically acceptable salt thereof, a pharmaceutical composition comprising them as an active ingredient, a MAPKAP-K2 (mitogen-activating protein kinase activating protein kinase 2) inhibitor comprising them as an active ingredient and a novel intermediate thereof. The present invention also relates to a therapeutic agent comprising these compounds as an active ingredient for neurodegenerative/neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).

BACKGROUND ART

MAPKAP-K2 (mitogen-activating protein kinase activating protein kinase 2) is a serine/threonine kinase and operates at immediate downstream of p38 kinase in a stress-induced MAPK pathway (FIG. 1).

This p38 kinase pathway is activated by various stress-related extracellular stimuli such as heat, ultraviolet ray, bacterial lipopolysaccharide or inflammatory cytokines. The activation of this pathway causes phosphorylation of transcription and initiation factors and affects cell division, apoptosis, cell differentiation, inflammatory response and infiltration of cancer cells (Martin-Blanco, Bioessays 22, 637-645).

p38 Kinase itself activates many protein kinases other than MAPKAP kinase, for example, Mnk1/2, PRAK and MSK1 (FIG. 1). This pathway is particularly important for discovery of novel anti-inflammatory drugs. A p38 kinase-selective inhibitor is effective for suppressing inflammatory cytokines in both cell base model and model animals of chronic inflammation (Lee et al., Immunopharmacology 47, 185-201 (2000)). However, a p38 kinase-knockout mouse is embryonic lethal. Moreover, it has been proved that cells derived from such an embryo exhibit a lot of anomaly in fundamental cellular responses. As another strategy for developing anti-inflammatory drugs, there may be mentioned a drug inhibiting this pathway in the level of MAPKAP-K2. MAPKAP-K2 exists in the nucleus in an unstimulated cell, and is transferred to cytosol when the cell is stimulated. It is known that this kinase phosphorylates many nuclear transcription factors and cytosolic proteins such as heat-shock protein involved in cell protection and 5-lipoxygenase involved in bioprotection and inflammation (Stokoe et al., FEBS Lett. 313, 307-313 (1992); Werz et al., Proc. Natl. Acad. Sci. USA 97, 5261-5266 (2000); Heindenreich et al., J. Biol. Chem. 274, 14434-14443 (1999); Tan et al., EMBO J. 15, 4629-4642 (1996); Neufeld, J. Biol. Chem. 275, 20239-20242 (2000)). All of these substrates contain a unique amino acid motif (XX-Hyd-XRXXSXX where Hyd represents a bulky hydrophobic residue) which is required for effective phosphorylation by MAPKAP-K2 (Stokoe et al., Biochem. J. 296, 843-849 (1993)).

MAPKAP-K2 is the only substrate of p38 kinase whose special function is currently identified. The special roll of MAPKAP-K2 in mediation of inflammatory response is remarkably demonstrated in a phenotype of MAPKAP-K2 knockout mouse (MAPKAP-K2^(−/−)) (Kotlyarov et al., Nature Cell Biol. 1, 94-97 (1999)). This mouse is not lethal and normal except for particularly reduced inflammatory response. Recently, it has been proved that lack of MAPKAP-K2 causes particular protection of neurons from ischemic brain injury (Wang et al., J. Biol. Chem. 277, 43968-43972 (29002)). It is considered that MAPKAP-K2 regulates translation and/or stabilization of mRNA of important inflammatory cytokines. This is likely because MAPKAP-K2 phosphorylates proteins which bind to AU-rich elements found in untranslated regions of these cytokines. Identification of these proteins is now under investigation.

Furthermore, it is reported that MAPKAP-K2 has activity of repairing anomaly in DNA induced by ultraviolet ray (Isaac A. Manke et al., Molecular Cell 17, 37-48 (2005)). Inhibition of MAPKAP-K2 activity may disable repairing damaged DNA and cause death in some types of cancer cell.

From the above, a MAPKAP-K2 inhibitor is effective for neurodegenerative/neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).

As MAPKAP-K2 inhibitors there have been disclosed in WO2004/054504, WO2004/054505, WO2004/055015, WO2004/055019, WO2004/058176, WO2004/058762, WO2004/099127, WO2005/009370, WO2005/007092, WO2004/076458 and WO2004/081013, but these compounds are different in the structure from the compound of the present invention.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel compound useful as a MAPKAP-K2 inhibitor.

Another object of the present invention is to provide a novel MAPKAP-K2 inhibitor or a novel therapeutic agent for neurodegenerative and/or neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD). A still other object of the present invention is to provide a novel intermediate of the novel MAPKAP-K2 inhibitor.

The present inventors pursued zealous study, found that novel pyrazolopyrimidine derivatives and pharmaceutically acceptable salts thereof represented by the following formula (1) exhibit excellent MAPKAP-K1 inhibitory activity, and accomplished the present invention.

Namely, the present invention is

<1> A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1):

[wherein, R¹ represents a hydrogen atom or a halogen; R² represents a hydrogen atom or a halogen; R³ represents a hydrogen atom, an optionally substituted C1-C1 alkyl group, an optionally substituted C1-C1 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR⁵; R⁵ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R⁶; R⁶ represents an optionally substituted C1-C8 alkyl group; n represents 0 or 1, or n represents 0 when R³ is —OR⁵; R⁴ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted heterocyclylalkyl group or an optionally substituted C7-C16 aralkyl group; the substituents in the optionally substituted C6-C14 aryl group as R⁴ are one or more substituents selected from the group consisting of halogen, —CN, —NO₂, —CHO, —OH, —COOH, optionally substituted C1-C8 alkyl group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)—R¹³³, —O—C(═O)R²⁶, —C(═O)OR²⁷, —NR²⁸C(═O)R²⁹, —NR³⁰R³¹, —C(═O)NR³²R³³, —NR³⁴C(═X¹)OR³⁵, —NR³⁶C(═X²)NR³⁷R³⁸, —NR³⁹—SO₂R⁴⁰, —S(O)_(r)—R⁴¹ and —SO₂NR⁴²R⁴³, wherein X¹ or X² represents O, S, N—CN or NH and r represents 0 to 2; W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group, and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group, —NR¹⁵⁰R¹⁵¹ or an optionally substituted phenoxy group and in this case m represents 1 to 4; R²⁶ to R⁴³, R³³, R¹⁵⁰ and R¹⁵¹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclylalkyl group, or, when R³⁰ and R³¹, R³² and R³³, R³⁷ and R³⁸, R⁴² and R⁴³ or R¹⁵⁰ and R¹⁵¹ are optionally substituted alkyl groups, the substituents in each combination may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; -A-B- represents —CH₂—CH(-Z¹)-, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂—, —CH═C(-Z²)— or —(CH₂)_(q)—C(═O)—; p represents 3 or 4 and q represents 1 or 2; Z¹ and Z² may be identical or different and each represents a hydrogen atom or —CH₂—OR¹¹; and R¹¹ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or a substituted silyl group.] <2> A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1):

[wherein, R¹ represents a hydrogen atom or a halogen; R² represents a hydrogen atom or a halogen; R³ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR⁵; R⁵ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R⁶; R⁶ represents an optionally substituted C1-C8 alkyl group; n represents 0 or 1 or n represents 0 and when R³ is —OR⁵; R⁴ represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted C7-C16 aralkyl group; the substituents in the optionally substituted C6-C14 aryl group as R⁴ are one or more substituents selected from the group consisting of halogen, —CN, —NO₂, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR⁷, —NR⁸C(═O)R⁹, —NR¹⁰R¹²⁷, —C(═O)NR¹²⁸R¹²⁹ and —SO₂NR¹³⁰R¹³¹; W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group or an optionally substituted phenoxy group and in this case m represents 1 to 4; R⁷ to R¹⁰ and R¹²⁷ to R¹³¹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group, or, when R¹⁰ and R¹²⁷, R¹²⁸ and R¹²⁹ or R¹³⁰ and R¹³¹ are optionally substituted alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; -A-B- represents —CH₂—CH(-Z³)-, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂—, —CH═C(-Z⁴)— or —(CH₂)_(q)—C(═O)—; p represents 3 or 4 and q represents 1 or 2; Z³ and Z⁴ may be identical or different and each represents a hydrogen atom or —CH₂—OR¹¹; and R¹¹ represents a hydrogen atom or an optionally substituted C1-C8 alkyl group.] <3> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to either <1> or <2>, wherein R¹ is a hydrogen atom. <4> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <3>, wherein R² is a hydrogen atom. <5> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <3>, wherein R² is a halogen. <6> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <5>, wherein R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group. <7> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <5>, wherein R³ is an unsubstituted C1-C4 alkyl group, a substituted C1-C4 alkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, phenyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, —CN, —CHO, —OH, —(C═O)OH, —(C═O)OR⁸⁶, —(C═O)NR⁸⁷R⁸⁸ and —NR⁸⁹R⁹⁰; R⁸⁶ represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group or a phenyl group; R⁸⁷ and R⁸⁸ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl group; R⁸⁹ represents a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a benzyl group; R⁹⁰ represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, or, when R⁸⁹ and R⁹⁰ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond; further this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which R⁸⁹ and R⁹⁰ bond), an unsubstituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —OH, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkoxy group and —NR⁹¹R⁹², wherein R⁹¹ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R⁹² represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), an unsubstituted heterocyclic group or a substituted heterocyclic group (wherein, when carbon atom(s) in the substituted heterocyclic group are substituted, the substituent(s) are 1 to 3 substituents selected from the group consisting of halogen, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, phenyl group, benzyl group, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁹³R⁹⁴, wherein R⁹³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R⁹⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, wherein, when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group). <8> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <5>, wherein R³ is an unsubstituted heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted saturated heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in the heterocycle and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group and tert-butoxycarbonyl group), a C1-C4 alkyl group substituted with one amino group or a C3-C8 cycloalkyl group substituted with one amino group. <9> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <5>, wherein R³ is a piperidyl group, a pyrrolidinyl group or a cyclohexyl group substituted with an amino group. <10> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <9>, wherein n is 0. <11> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group. <12> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR⁷ and —C(═O)NR⁹R¹⁰. <13> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group and —O—(CH₂)_(m)—W. <14> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more —O—(CH₂)_(m)—W, wherein W is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted heterocyclic group or an optionally substituted C1-C8 alkoxy group. <15> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <8>, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, optionally substituted C6-C14 aryl group and optionally substituted heterocyclic group. <16> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —C(═O)OR⁷ and —C(═O)NR⁹R¹⁰. <17> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W and —C(═O)OR¹¹³, wherein W represents a hydrogen atom, an optionally substituted C1-C4 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted monocyclic or bicyclic heterocyclic group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4, and R¹¹³ represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted phenyl group). <18> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted phenyl group (wherein the substituent is one —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4). <19> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, optionally substituted phenyl group and optionally substituted monocyclic or bicyclic heterocyclic group). <20> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, —C(═O)OR¹¹³ and —C(═O)NR¹¹⁸R¹¹⁹, wherein R¹¹³, R¹¹⁸ and R¹¹⁹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group; and when R¹¹⁸ and R¹¹⁹ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which they bond). <21> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted heterocyclic group. <22> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein, when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, C1-C8 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C8 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, phenyl group, monocyclic or bicyclic heterocyclic group, —C(═O)OR¹²², —NR¹²³R¹²⁴ and —C(═O)NR¹²⁵R¹²⁶ wherein R¹²³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, R¹²⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, R¹²² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and R¹²⁵ and R¹²⁶ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group; when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group). <23> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein the bicyclic heteroaryl group means a bicyclic heteroaryl group wherein a phenyl group is fused with an aromatic heterocycle containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens; when nitrogen atom(s) in the heterocycle are substituted, the substituent represents one or more C1-C4 alkyl group). <24> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C7-C16 aralkyl group or an optionally substituted heterocyclylalkyl group. <25> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <10>, wherein R⁴ is an optionally substituted heterocyclylalkyl group. <26> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <25>, wherein -A-B- is —CH₂—CH₂—, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂— or —CH═CH—. <27> The pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <25>, wherein -A-B- is —CH₂—CH₂. <28> A pyrazolopyrimidine derivative represented by formula (2):

[wherein, R¹, R², R³, R⁴, n and -A-B- are as defined in either claim 1 or 2, and Boc represents tert-butoxycarbonyl]. <29> The pyrazolopyrimidine derivative according to <28>, wherein R¹ and R² are a hydrogen atom. <30> The pyrazolopyrimidine derivative according to <28>, wherein R¹ is a hydrogen atom and R² is a halogen. <31> The pyrazolopyrimidine derivative according to any of <28> to <30>, wherein R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted cyclohexyl group or an optionally substituted heterocyclic group (wherein the heterocyclic group means a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S). <32> The pyrazolopyrimidine derivative according to any of <28> to <30>, wherein R³ is an unsubstituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in a saturated heterocyclic group and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group), a C1-C4 alkyl group substituted with an amino group or a C3-C8 alkyl group substituted with an amino group. <33> The pyrazolopyrimidine derivative according to any of <28> to <32>, wherein R⁴ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group. <34> The pyrazolopyrimidine derivative according to any of <28> to <32>, wherein R⁴ is an optionally substituted phenyl group or an optionally substituted bicyclic heteroaryl group. <35> The pyrazolopyrimidine derivative according to any of <28> to <32>, wherein R⁴ is an optionally substituted phenyl group (wherein the substituents are one or more —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4, or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4). <36> The pyrazolopyrimidine derivative according to any of <28> to <32>, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens.). <37> The pyrazolopyrimidine derivative according to any of <28> to <36>, wherein -A-B- is —CH₂—CH₂—, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂— or —CH═CH—. <38> The pyrazolopyrimidine derivative according to any of <28> to <36>, wherein -A-B- is —CH₂—CH₂. <39> The pyrazolopyrimidine derivative according to any of <28> to <38>, wherein n is 0. <40> A pharmaceutical composition comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <27> and a pharmaceutically acceptable carrier. <41> A MAPKAP-K2 inhibitor comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <27> as an active ingredient. <42> A therapeutic agent comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to any of <1> to <27> as an active ingredient for neurodegenerative and/or neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma or chronic obstructive pulmonary disease (COPD). <43> The therapeutic agent according to <42>, wherein the autoimmune disease is rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, graft-versus-host disease, diabetes mellitus or Crohn's disease.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a FIGURE illustrating p38MAPK cascade.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds represented by formula (1) in the present invention are defined as follows.

“Alkyl group” in the present specification represents either a linear or branched alkyl group. Preferably it is an alkyl group having 1 to 8 carbon atoms. For example, although not limited thereto, there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 4-methylpentyl, 3-hexyl, n-hexyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, 2-methyl-2-hexyl, 6-methylheptyl and n-octyl. More preferably, it is an alkyl group having 1 to 6 carbon atoms, and still more preferably it is an alkyl group having 1 to 4 carbon atoms. For example, although not limited thereto, there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

“Alkenyl group” in the present specification represents a linear, branched or cyclic alkenyl group having one or more C—C double bonds. When the group exists as either trans or cis form, it includes both isomers. Preferably it is an alkenyl group having 2 to 8 carbon atoms. For example, although not limited thereto, there may be mentioned vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 1-butenyl, 2-methyl-1-propenyl, 2-methyl-3-pentenyl, 1-pentenyl, 2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl, 2-heptenyl, 2-octenyl, 3-cyclopentenyl, 1,3-butadienyl and 1,5-hexadienyl. More preferably, it is an alkenyl group having 2 to 6 carbon atoms, and still more preferably it is an alkenyl group having 2 to 4 carbon atoms. For example, although not limited thereto, there may be mentioned vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 1-butenyl and 2-methyl-1-propenyl.

“Alkynyl group” in the present specification represents either a linear or a branched alkynyl group having one or more C—C triple bonds. Preferably it is an alkynyl group having 2 to 8 carbon atoms. For example, although not limited thereto, there may be mentioned ethynyl, 2-propynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-hexynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-pentynyl, 2-petynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-heptynyl and 2-octynyl. More preferably, it is an alkynyl group having 2 to 6 carbon atoms, and still more preferably it is an alkynyl group having 2 to 4 carbon atoms. For example, although not limited thereto, there may be mentioned ethynyl, 2-propynyl, 1-propynyl and 1-butynyl.

“Cycloalkyl group” in the present specification represents a cyclic alkyl group. Preferably it is a cycloalkyl group having 3 to 8 carbon atoms. For example, although not limited thereto, there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

“Aryl group” in the present specification represents a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group having 6 or 14 carbon atoms; or an aromatic hydrocarbon group having totally 6 to 14 carbon atoms wherein such an aromatic hydrocarbon group is fused with one or more saturated or partially saturated carbocycles. For example, although not limited thereto, there may be mentioned phenyl, naphthyl, anthracenyl, 5-indanyl and 5,6,7,8-tetrahydro-2-naphthyl. Preferably it is an aryl group having 6 to 10 carbon atoms. For example, although not limited thereto, there may be mentioned phenyl, naphthyl, 5-indanyl and 5,6,7,8-tetrahydro-2-naphthyl. More preferably it is phenyl.

“Heterocyclic group” in the present specification means a monovalent group derived from a 3- to 14-membered monocyclic, bicyclic or tricyclic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S. The heterocyclic group may be completely saturated, partially saturated or aromatized. The heterocyclic group may contain one or two —C(═O) or —C(═S)—. As example of the heterocyclic group, although not limited thereto, there may be mentioned a monovalent group derived from furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isoxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzoxazole, chroman, isochroman, quinoline, decahydroquinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazne, quinuclidine, acridine, carbazole, cinnoline, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, indolizine, indazole, isoindole, isoxazole, isobenzofuan, naphthyridine, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phthalazine, quinolizine, tetrahydrofuran, tetrazine, thiadiazine, thiatriazole, thiazine, thianaphthalene, triazine, 1,3-dioxane, 2,5-dihydrofuran, oxazoline, trithiane, piperidin-2-one, 3H-isobenzofuran-1-one, 8-caprolactam, 2-furanone, 2-pyrrolidone, tetrahydro-3H-pyrazol-3-one, piperazin-2-one, coumarin, tetrahydro-2-pyrimidinone, glutarimide or morpholine-3,5-dione. Preferably it means a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S.

“Heteroaryl group” in the present specification means, among the above “heterocyclic group”, a monocyclic, bicyclic or tricyclic heterocyclic group wherein the ring forming a monovalent group is aromatized. In the case of a bicyclic or tricyclic group, rings other than the ring forming a monovalent group may be completely saturated, partially saturated or aromatized. The heteroaryl group may contain one or two —C(═O)— or —C(═S)—. For example, although not limited thereto, there may be mentioned a monovalent group derived from furan, thiophene, pyrrole, oxazole, thiazole, isothiazole, isoxazole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzoxazole, indazole, isobenzofuran, quinoline, isoquinoline, quinazoline, purine or acridine, 7-chromanyl, 6-isochromanyl and 5-indolinyl. Preferably it means a bicyclic heteroaryl group wherein a phenyl group is fused with a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S. As examples of such a group, although not limited thereto, there may be mentioned 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 5-benzothienyl, 6-benzofuranyl, 6-indazolyl, 5-quinolyl, 7-phthalazinyl, 6-quinoxalinyl, 6-quinazolinyl, 6-cinnolinyl, 7-chromanyl, 5-indolinyl and 6-isoindolinyl. More preferably, it means a bicyclic heteroaryl group wherein a phenyl group is fused with a heteroaryl containing 1 or 2 heteroatoms selected from the group consisting of N, O and S. As examples of such a group, although not limited thereto, there may be mentioned 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 5-benzothienyl, 6-benzofuranyl, 6-indazolyl, 5-quinolyl, 7-phthalazinyl, 6-quinoxalinyl, 6-quinazolinyl and 6-cinnolinyl.

“Saturated heterocyclic group” in the present specification represents, among the above “heterocyclic group”, a monocyclic, bicyclic or tricyclic heterocyclic group wherein the ring forming a monovalent group is completely or partially saturated. In the case of a bicyclic or tricyclic group, rings other than the ring forming a monovalent group may be completely saturated, partially saturated or aromatized. The saturated heterocyclic group may contain one or two —C(═O)— or —C(═S)—. For example, although not limited thereto, there may be mentioned a monovalent group derived from pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine or tetrahydrofuran, 3-chromanyl and 3-indolyl. Preferably it represents a 5- to 8-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S. For example, although not limited thereto, there may be mentioned a monovalent group derived from pyrrolidine, imidazolidine, pyrazolidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine or tetrahydrofuran.

“Heterocyclylalkyl group” in the present specification represents a group composed of a heterocyclic group and an alkyl group. Here, the heterocyclic group and the alkyl group correspond to “heterocyclic group” and “alkyl group” defined above, respectively. As preferred examples of the heterocyclylalkyl group, there may be mentioned a group composed of a group included in the above definition and one of the preferred groups or a combination of one of the referred groups for each moiety. Preferably, it is a group composed of a 3- to 10-membered monocyclic or bicyclic “heterocyclic group” containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and an “alkyl group” having 1 to 8 carbon atoms. More preferably, it is a group containing a combination of a 3- to 10-membered monocyclic or bicyclic “heterocyclic group” containing 1 to 4 heteroatoms selected from the group consisting of N, O and S and an “alkyl group” having 1 to 4 carbon atoms. As examples, although not limited thereto, there may be mentioned (2-furyl)methyl, (3-thienyl)methyl, (5-isobenzofuranyl)methyl, (5-benzothienyl)methyl, (6-benzoxazolyl)methyl, 2-(4-morpholyl)ethyl, 2-(3-thienyl)ethyl, 2-(1-pyrazinyl)ethyl, 3-(2-pyridyl)propyl and 3-(4-piperidyl)propyl.

“Aralkyl group” in the present specification represents a group composed of an aryl group and an alkyl group. Here, the aryl group and the alkyl group correspond to “aryl group” and “alkyl group” defined above, respectively. Preferably it is a group composed of an “aryl group” having 6 to 10 carbon atoms and an “alkyl group” having 1 to 8 carbon atoms. As examples, although not limited thereto, there may be mentioned benzyl, phenethyl, (2-naphthyl)methyl, 3-phenylpropyl, 4-phenylbutyl and 5-(1-naphthyl)pentyl. More preferably, it is a group composed of a phenyl group and an alkyl group having 1 to 4 carbon atoms. As examples of such a group, although not limited thereto, there may be mentioned benzyl, phenethyl, (2-naphthyl)methyl, 3-phenylpropyl and 4-phenylbutyl.

“Alkoxy group” in the present specification represents a linear, branched or cyclic alkoxy group. Preferably it is an alkoxy group having 1 to 8 carbon atoms. As examples, although not limited thereto, there may be mentioned methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy and n-heptyloxy. More preferably, it is an alkoxy group having 1 to 6 carbon atoms, and still more preferably it is an alkoxy group having 1 to 4 carbon atoms. As examples of such a group, although not limited thereto, there may be mentioned methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

“Halogen” in the present specification represents F, Cl, Br or I. Preferably it is F, Cl or Br. In the present specification, the FIGURE following “C” in, for example, “C1” represents the number of carbon atoms, and “C1-C6” represents the range of number of carbon atoms of 1 to 6. Needless to say, in the present invention, each group different in number of carbon atoms means the same type of group having each number of carbon atoms. For example, “C1-C6 alkyl group” means an alkyl group, which is defined for “C1-C8 alkyl group”, having 1 to 6 carbon atoms. Numbers of carbon atoms in other groups are interpreted in the same way.

“Substituted silyl group” in the present specification represents a silyl group that can be used as a protecting group for a hydroxyl group. Preferably it is trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triethylsilyl, and more preferably it is tert-butyldimethylsilyl.

The substituents in the “optionally substituted alkyl group” in the present invention are one or more substituent(s) selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R¹⁰, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁵¹, —(C═O)NR⁵²R⁵³, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR¹²R¹³. Preferably, they are one or more substituents selected from the group consisting of a halogen, —OH, —(C═O)OH, a phenyl group, a C1-C4 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR¹²R¹³. The preferred number of substituents is 1 to 3. Here, R¹² represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹³ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. When R¹² and R¹³ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R¹² and R¹³ bond. R⁵⁰ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁵¹ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁵² and R⁵³ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group. When R⁵² and R⁵³ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R⁵² and R⁵³ bond. Preferably each of R⁵² and R⁵³, which may be identical or different, is a hydrogen atom or a C1-C4 alkyl group.

The substituents in “optionally substituted alkenyl” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁵⁴, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁵⁵, —(C═O)NR⁵⁶R⁵⁷, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁴⁴R⁴⁵. Preferably, they are one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a phenyl group and an amino group. The preferred number of substituents is 1 to 3. Here, R⁴⁴ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁴⁵ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁵⁴ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁵⁵ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁵⁶ and R⁵⁷ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group. Preferably they are a hydrogen atom or a C1-C4 alkyl group. The substituents in “optionally substituted alkynyl” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁵⁸, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁵⁹, —(C═O)NR⁶⁰R⁶¹, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁴⁶R⁴⁷. Preferably, they are one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a phenyl group and an amino group. Preferably the number of substituents is 1 to 3. Here, R⁴⁶ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁴⁷ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁵⁸ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁵⁹ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁶⁰ and R⁶¹ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group.

The substituents in “optionally substituted cycloalkyl group” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁶, —(C═O)NR⁶⁴R⁶⁵, a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, a C1-C8 alkoxy group and —NR¹⁴R¹⁵. Preferably they are one or more substituents selected from the group consisting of a halogen, —OH, —(C═O)OH, a C1-C4 alkyl group, a phenyl group and —NR¹⁴R¹⁵. More preferably they are one or more substituents selected from the group consisting of —OH, a C1-C4 alkoxy group and —NR¹⁴R¹⁵. Preferably the number of substituents is 1 to 3. Here, R¹⁴ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁵ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁶² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁶³ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁶⁴ and R⁶⁵ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group. When R⁶⁴ and R⁶⁵ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R⁶⁴ and R⁶⁵ bond. Preferably, R⁶⁴ and R⁶⁵, which may be identical or different, are a hydrogen atom or a C1-C4 alkyl group.

The substituents in “optionally substituted aralkyl group” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁶⁶, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁶⁷, —(C═O)NR⁶⁸R⁶⁹, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogen atoms and —NR¹⁶R¹⁷. Preferably, they are one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a C1-C8 alkoxy group, a phenyl group and an amino group. Preferably the number of substituents is 1 to 3. Here, R¹⁶ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁷ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁶⁶ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁶⁷ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁶⁸ and R⁶⁹ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group.

The substituents in “optionally substituted alkoxy group” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁷⁰, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁷¹, —(C═O)NR⁷²R⁷³, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group and —NR¹⁸R¹⁹. Preferably they are one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a phenyl group and an amino group. Preferably the number of substituents is 1 to 3. Here, R¹⁸ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁹ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁷⁰ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁷¹ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁷² and R⁷³ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group, and preferably each of them is a hydrogen atom or a C1-C4 alkyl group.

The substituents in “optionally substituted phenoxy group” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁷⁴, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁷⁵, —(C═O)NR⁷⁶R⁷⁷, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group and —NR²⁰R²¹. Preferably, they are one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group, a phenyl group and an amino group. Preferably the number of substituents is 1 to 3. Here, R²⁰ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R²¹ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁷⁴ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁷⁵ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁷⁶ and R⁷⁷ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group.

The substituents on carbon atom(s) in “optionally substituted heterocyclic group” in the present invention are one or more substituents selected from the group consisting of a halogen, —(C═O)—R⁷⁸, —CN, —NO₂, —OH, —(C═O)OH, —(C═O)OR⁷⁹, —(C═O)NR⁸⁰R⁸¹, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C2-C8 alkenyl, a C2-C8 alkynyl, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a heterocyclic group, a C7-C16 aralkyl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR²²R²³. Preferably they are one or more substituents selected from the group consisting of a halogen, —CN, —NO₂, —OH, —(C═O)OH, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR²²R²³Still more preferably they are one or more substituents selected from the group consisting of a halogen, —(C═O)OH, a C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a phenyl group, a C1-C4 alkoxy group and an amino group. Preferably the number of substituents is 1 to 3. Here, R²² represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group and a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R²³ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁷⁸ represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁷⁹ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁸⁰ and R⁸¹ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group. When nitrogen atom(s) in the heterocyclic group are substituted, the substituents are one or more substituents selected from the group consisting of a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group.

When R⁴ is an “optionally substituted aryl group” in the present invention, the substituents are one or more substituents selected from the group consisting of a halogen, —CN, —NO₂, —CHO, —OH, —COOH, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, —O—(CH₂)_(m)—W, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, —C(═O)—R¹³³, —O—C(═O)R²⁶, —C(═O)OR²⁷, —NR²⁸C(═O)R²⁹, —NR³⁰R³¹, —C(═O)NR³²R³³, —NR³⁴—C(═X)OR³⁵, —NR³⁶—C(═X)NR³⁷R³⁸, —NR³⁹—SO₂R⁴⁰, —S(O)_(r)—R⁴¹ and —SO₂NR⁴²R⁴³. Preferably they are one or more substituents selected from the group consisting of a halogen, —CN, —NO₂, an optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, an optionally substituted phenyl group, an optionally substituted heterocyclic group, —(C═O)OR⁷, —NR⁷(C═O)R⁸, —NR⁹R¹⁰, —(C═O)NR⁹R¹⁰ and —SO₂NR⁹R¹⁰. More preferably they are one or more substituents selected from the group consisting of a halogen, an optionally substituted C1-C4 alkyl group, —O—(CH₂)_(m)—W and —C(═O)OR²⁷, and —O—(CH₂)_(m)—W is still more preferred. The number of substituents is 1 to 3, and preferably 1.

W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group and m is 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group or an optionally substituted phenoxy group and m is 1 to 4. Preferably,

W is a hydrogen atom, an optionally substituted C1-C4 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted monocyclic or bicyclic heterocyclic group and m is 0 to 4; or W is an optionally substituted C1-C4 alkoxy group and m is 1 to 4. More preferably, W is a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4; or W is an optionally substituted C1-C4 alkoxy group and m is 1 to 4. Still more preferably, W is a C1-C4 alkyl group and m is 0; or W is a C1-C4 alkoxy group and m is 2.

R⁷, R⁸, R⁹ and R¹⁰ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group. When R⁹ and R¹⁰ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R⁹ and R¹⁰ bond. Preferably R⁷, R⁸, R⁹ and R¹⁰, which may be identical or different, are a hydrogen atom or an optionally substituted C1-C4 alkyl group.

R²⁶—R⁴³, R³³, R¹⁵⁰ and R¹⁵¹ may be identical or different and each represents is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclylalkyl group. When R³⁰ and R³¹R³² and R³³R³⁷ and R³⁸, R⁴² and R⁴³, or R¹⁵⁰ and R¹⁵¹ are alkyl groups, the substituents in each combination may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which the substituents bond. Preferably R²⁶—R⁴³, R¹³³, R¹⁵⁰ and R¹⁵¹, which may be identical or different, are a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group. More preferably they are a hydrogen atom or an optionally substituted C1-C4 alkyl group. Each of X¹ and X² represents O, S, N—CN or NH, and preferably O. r represents an integer ranging from 0 to 2, and preferably it is 0 or 2.

The substituents in “optionally substituted aryl group” other than “optionally substituted aryl group as R⁴” in the present invention are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R⁸², —NO₂, —OH, —(C═O)OH, —(C═O)OR⁸³, —(C═O)NR⁸⁴R⁸⁵, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR²⁴R²⁵. Preferably they are one or more substituents selected from the group consisting of a halogen, —CN, —OH, —(C═O)OH, a C1-C6 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C6 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR²⁴R²⁵. A halogen is further preferred. The number of substituents is 1 to 3 and preferably 1. Here, R²⁴ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R²⁵ represents a hydrogen atom, a C1-C8 alkyl group or a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁸² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁸³ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R⁸⁴ and R⁸⁵ may be identical or different and each represents is a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group. Preferably they are a hydrogen atom or a C1-C4 alkyl group.

The substituents on carbon atom(s) in “optionally substituted heterocyclylalkyl group” in the present invention are one or more substituents selected from the group consisting of a halogen, —(C═O)—R¹²⁷, —CN, —NO₂, —OH, —(C═O)OH, —(C═O)OR¹²⁸, —(C═O)NR¹²⁹R¹³⁰, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR¹³¹R¹³². Preferably the alkyl moiety in the heterocyclylalkyl group is unsubstituted and substituents on carbon atom(s) in the heterocycle moiety are one or more substituents selected from the group consisting of a halogen, —(C═O)OH, a C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C4 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR¹³¹R¹³², further preferably, one or more substituents selected from the group consisting of a halogen, a C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 9 halogens. Preferably the number of substituents is 1 to 3. Here, R¹³¹ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹³² represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹²⁷ represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R¹²⁸ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a C6-C14 aryl group, and preferably it is a C1-C4 alkyl group. R¹²⁹ and R¹³⁰ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a C6-C14 aryl group or an aralkyl group. Preferably they are a hydrogen atom or a C1-4 alkyl group. When nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of a C1-4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group.

R¹ is preferably hydrogen.

R² is preferably hydrogen.

R³ is preferably an optionally substituted C1-8 alkyl group, an optionally substituted C3-8 cycloalkyl group or an optionally substituted heterocyclic group.

Among the optionally substituted C1-C8 alkyl groups, which are preferred groups as R³, as more preferred example, there may be mentioned unsubstituted C1-C6 alkyl groups and substituted C1-C6 alkyl groups. (Here, the substituents are 1 to 3 substituents selected from the group consisting of a halogen, a phenyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C4 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens, —CN, —CHO, —OH, —(C═O)OH, —(C═O)OR⁸⁶, —(C═O)NR⁸⁷R⁸⁸ and —NR⁸⁹R⁹⁰. Further preferably they are 1 to 3 substituents selected from the group consisting of a phenyl group, a C1-C4 alkoxy group, —CHO and —NR⁸⁹R⁹⁰. More preferably the substituent is one —NR⁸⁹R⁹⁰. Preferably the number of substituents is 1 to 3 for halogen or 1 for the others. R⁸⁶ represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R⁸⁷ and R⁸⁸ may be identical or different, and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group. R⁸⁹ represents a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁹⁰ represent a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. When R⁸⁹ and R⁹⁰ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further, this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R⁸⁹ and R⁹⁰ bond.)

Among the optionally substituted C3-C8 cycloalkyl groups, which are preferred groups as R³, as more preferred examples, there may be mentioned unsubstituted C3-C8 cycloalkyl groups and substituted C3-C8 cycloalkyl groups. (Here, the substituents are 1 to 3 substituents selected from the group consisting of a halogen, —OH, —(C═O)OH, a C1-C4 alkyl group, a phenyl group, a C1-C4 alkoxy group and —NR⁹¹R⁹². Preferably they are 1 to 3 substituents selected from the group consisting of —OH, —(C═O)OH and —NR⁹¹R⁹². More preferably it is one —NR⁹¹R⁹². Preferably the number of substituents is 1 to 3 for halogens or 1 for the others. Here, R⁹¹ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁹² represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.)

Among the optionally substituted heterocyclic groups, which are preferred groups as R³, as more preferred examples, there may be mentioned an unsubstituted monocyclic heterocyclic group, an unsubstituted bicyclic heterocyclic group, a substituted monocyclic heterocyclic group and a substituted bicyclic heterocyclic group, and more preferably there may be mentioned an unsubstituted monocyclic heterocyclic group and a substituted monocyclic heterocyclic group. Here, when carbon atom(s) in the substituted monocyclic heterocyclic group or substituted bicyclic heterocyclic group are substituted, the substituent(s) are 1 to 3 substituents selected from the group consisting of a halogen, —(C═O)OH, a C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a phenyl group, a benzyl group, a C1-C4 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁹³R⁹⁴. Preferably they are 1 to 3 substituents selected from the group consisting of a C1-C4 alkyl group and an amino group. Preferably the number of substituents is 1 to 3 for halogens or 1 for the others. Here, R⁹³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R⁹⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. When nitrogen atom(s) in the heterocyclic group are substituted, the substituents are one or more substituents selected from the group consisting of a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group. Preferably the substituent is a C1-C4 alkyl group, a benzyl group or a tert-butoxycarbonyl group and more preferably a C1-C4 alkyl group or a tert-butoxycarbonyl group.

Preferably, R³ is an unsubstituted 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, a C1-C4 alkyl group substituted with one amino group or a C3-C8 cycloalkyl group substituted with one amino group.

More preferably, R³ is an unsubstituted 5- to 8-membered monocyclic saturated heterocyclic group containing one nitrogen atom, a C1-C4 alkyl group substituted with one amino group or a C3-C8 cycloalkyl group substituted with one amino group.

Still more preferably, R³ is a piperidyl group, a pyrrolidinyl group or a cyclohexyl group substituted with one amino group.

Furthermore preferably R³ is a piperidyl group or a pyrrolidinyl group.

Preferably R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted heterocyclylalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group.

Among the optionally substituted C1-C8 alkyl groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned unsubstituted C1-C8 alkyl groups and substituted C1-C8 alkyl groups. (Here, the substituents are 1 to 3 substituents selected from the group consisting of a halogen, —(C═O)—R⁹⁵, —OH, —(C═O)OH, —(C═O)OR⁹⁶, —(C═O)NR⁹⁷R⁹⁸, a C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁹⁹R¹⁰⁰. More preferably, they are 1 to 3 substituents selected from the group consisting of a halogen, a C3-C8 cycloalkyl group, a phenyl group, a C1-C8 alkoxy group and a C1-C4 alkoxy group substituted with 1 to 9 halogens. Preferably the number of the substituents is 1 to 3 for halogens or 1 for the others. R⁹⁵ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R⁹⁶ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R⁹⁷ and R⁹⁸ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl group. When R⁹⁷ and R⁹⁸ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R⁹⁷ and R⁹⁸ bond. Preferably R⁹⁷ and R⁹⁸, which may be identical or different, are a hydrogen atom or a C1-C4 alkyl group. R⁹⁹ represents a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁰⁰ represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group.)

Among the optionally substituted C3-C8 cycloalkyl groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned unsubstituted C3-C8 cycloalkyl groups and substituted C3-C8 cycloalkyl groups. (Here, the substituents are 1 to 3 substituents selected from the group consisting of a halogen, —(C═O)—R¹⁰¹, —OH, —(C═O)OH, —(C═O)OR¹⁰², —(C═O)NR¹⁰³R¹⁰⁴, a C1-C8 alkyl group, a C6-C14 aryl group, a C1-C8 alkoxy group and —NR¹⁰⁵R¹⁰⁶. More preferably they are 1 to 3 substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a C1-C4 alkoxy group and a phenyl group. Preferably the number of the substituents is 1 to 3 for halogens or 1 for the others. Here, R¹⁰⁵ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁰⁶ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹⁰¹ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R¹⁰² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R¹⁰³ and R¹⁰⁴ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group. When R¹⁰³ and R¹⁰⁴ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which R¹⁰³ and R¹⁰⁴ bond. Preferably each of R¹⁰³ and R¹⁰⁴, which may be identical or different, is a hydrogen atom or a C1-C4 alkyl group.)

Among the optionally substituted aralkyl groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned an aralkyl group composed of an unsubstituted C1-C4 alkyl group and an unsubstituted phenyl group or an aralkyl group composed of an unsubstituted C1-C4 alkyl group and a substituted phenyl group. Here, the substituents in the substituted phenyl group are one or more substituents selected from the group consisting of a halogen, —CN, —CHO, —(C═O)—R¹⁰⁷, —NO₂, —OH, —(C═O)OH, —(C═O)OR¹⁰⁸, —(C═O)NR¹⁰⁹R¹¹⁰, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C3-C8 cycloalkyl group, a phenyl group, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR¹¹¹R¹¹². Preferably they are 1 to 3 substituents selected from the group consisting of a halogen, a C1-C4 alkyl group, a C1-C8 alkoxy group, —(C═O)OR¹⁰⁸ and —(C═O)NR¹⁰⁹R¹¹⁰. Preferably the number of the substituents is 1 to 3 for halogens or 1 for the others. R¹¹¹ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹¹² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group or a phenyl group. R¹⁰⁷ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R¹⁰⁸ represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R¹⁰⁹ and R¹¹⁰ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group.

Among the optionally substituted heterocyclylalkyl groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned unsubstituted heterocyclylalkyl groups and substituted heterocyclylalkyl groups. More preferably there may be mentioned a heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and an unsubstituted heteroaryl group and a heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and a substituted heteroaryl group. Furthermore preferably there may be mentioned a heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and an unsubstituted monocyclic or bicyclic heteroaryl group and a heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and a substituted monocyclic or bicyclic heteroaryl group. Here, in the substituted heterocyclic group, the heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and a substituted heteroaryl group or the heterocyclylalkyl group composed of an unsubstituted C1-C4 alkyl group and a substituted monocyclic or bicyclic heteroaryl group, the substituents on carbon atom(s) are one or more substituents selected from the group consisting of a halogen, —(C═O)OH, a C1-C4 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C4 alkoxy group and a C1-C4 alkoxy group substituted with 1 to 9 halogens. Preferably, the alkyl moiety in the heterocyclylalkyl group is unsubstituted and the substituents on carbon atom(s) in the heterocyclic group are one or more substituents selected form the group consisting of a halogen, a C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 9 halogens. Preferably the number of the substituents is 1 to 3. When nitrogen atom(s) in the heterocyclic group are substituted, the substituents are one or more substituents selected from the group consisting of a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group and a benzyloxycarbonyl group. More preferably, the substituent is a C1-C4 alkyl group or a tert-butoxycarbonyl group.

Among the optionally substituted C6-C14 aryl groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned unsubstituted C6-C10 aryl groups and substituted C6-C10 aryl groups, and more preferably there may be mentioned an unsubstituted phenyl group and a substituted phenyl group. Here, the substituents in the substituted C6-C10 aryl group or the substituted phenyl group are 1 to 3 substituents selected from the group consisting of a halogen, —CN, —NO₂, an optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, an optionally substituted phenyl group, an optionally substituted heterocyclic group, —(C═O)OR¹¹³, —NR¹¹⁴(C═O)R¹¹⁵, —NR¹¹⁶R¹¹⁷, —(C═O)NR¹¹⁸R¹¹⁹ and —SO₂NR¹²⁰R¹²¹. More preferably they are 1 to 3 substituents selected from the group consisting of a halogen, an optionally substituted C1-C4 alkyl group, —O—(CH₂)_(m) W and —(C═O)OR¹¹³. Still more preferably the substituent is one —O—(CH₂)_(m)—W. Preferably the number of the substituents is 1.

W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C10 aryl group or an optionally substituted heterocyclic group and in this case m is 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group, —NR¹⁵⁰R¹⁵¹ or an optionally substituted phenoxy group and in this case m is 1 to 4. Preferably W is a hydrogen atom, an optionally substituted C1-C4 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted monocyclic or bicyclic heterocyclic group and m is 0 to 4; or W is an optionally substituted C1-C4 alkoxy group and m is 1 to 4. More preferably, W is a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4; or W is an optionally substituted C1-C4 alkoxy group and m is 1 to 4. Furthermore preferably W is a C1-C4 alkyl group and m is 0; or W is a C1-C4 alkoxy group and m is 2.

R¹¹³-R¹²¹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclylalkyl group; or when R¹¹⁶ and R¹¹⁷, R¹¹⁸ and R¹¹⁹, or R¹²⁰ and R¹²¹ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond. Further this ring may contain 1 or 2 heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom besides the nitrogen atom to which these substituents bond. Preferably R¹¹³-R¹²¹, which may be identical or different, are a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group. More preferably R¹¹³-R¹²¹ which may be identical or different, are a hydrogen atom or an optionally substituted C1-C4 alkyl group, and still more preferably R¹¹³-R¹²¹, which may be identical or different, are a hydrogen atom or a C1-C4 alkyl group.

Among the optionally substituted heterocyclic groups, which are preferred groups as R⁴, as more preferred examples, there may be mentioned unsubstituted monocyclic heterocyclic groups, unsubstituted bicyclic heterocyclic groups, substituted monocyclic heterocyclic groups and substituted bicyclic heterocyclic groups. Unsubstituted bicyclic heteroaryl groups and substituted bicyclic heteroaryl groups are more preferred. Here, in the substituted monocyclic heterocyclic group, the substituted bicyclic heterocyclic group or the substituted bicyclic heteroaryl group, when carbon atom(s) are substituted, the substituent(s) are 1 to 3 substituents selected from the group consisting of a halogen, —CN, —NO₂, a C1-C8 alkyl group, a C1-C4 alkyl group substituted with 1 to 9 halogens, a C1-C8 alkoxy group, a C1-C4 alkoxy group substituted with 1 to 9 halogens, a phenyl group, a monocyclic or bicyclic heterocyclic group, —(C═O)OR¹²², —NR¹²³R¹²⁴ and —(C═O)NR¹²⁵R¹²⁶. Preferably they are 1 to 3 substituents selected from the group consisting of a halogen, a C1-C4 alkyl group and a C1-C4 alkyl group substituted with 1 to 9 halogens. More preferably the substituent is one C1-C4 alkyl group. Preferably the number of substituents is 1. Here, R¹²³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹²⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, and preferably it is a hydrogen atom or a C1-C4 alkyl group. R¹²² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and preferably it is a C1-C4 alkyl group. R¹²⁵ and R¹²⁶ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group, and preferably they are a hydrogen atom or a C1-C4 alkyl group. When nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group. Preferably the substituent is a C1-C4 alkyl group or a tert-butoxycarbonyl group.

More preferably R⁴ is an unsubstituted phenyl group, a phenyl group substituted with one —O—(CH₂)_(m)—W, an unsubstituted bicyclic heteroaryl group, a bicyclic heteroaryl group substituted with C1-C4 alkyl group(s) or a bicyclic heteroaryl group substituted with C1-C4 alkyl group(s) substituted with 1 to 9 halogens. (Here, W represents a C1-C4 alkyl group (in this case m is 0) or a C1-C4 alkoxy group (in this case m is 2). The bicyclic heteroaryl group means a bicyclic heteroaryl group wherein a phenyl group is fused with a heterocycle containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and preferably it is a bicyclic heteroaryl group wherein a phenyl group is fused with a heterocycle containing 1 or 2 heteroatoms selected from the group consisting of N, O and S.).

Still more preferably R⁴ is an unsubstituted phenyl group, a phenyl group substituted with one —O—(CH₂)_(m)—W, an unsubstituted bicyclic heteroaryl group, a bicyclic heteroaryl group substituted with one C1-C4 alkyl group or a bicyclic heteroaryl group substituted with one C1-C4 alkyl group substituted with 1 to 9 halogens (Here, W represents a C1-C4 alkyl group (in this case m is 0) or a C1-C4 alkoxy group (in this case m is 2). As the bicyclic heteroaryl group, there may be mentioned 5-benzothiazolyl, 6-benzothiazolyl, 5-benzoxazolyl, 6-benzoxazolyl, 5-benzothienyl, 6-benzothienyl, 5-benzofuranyl, 6-benzofuranyl, 5-indazolyl, 6-indazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 5-indolyl and 6-indolyl.)

Furthermore preferably R⁴ is an unsubstituted phenyl group, a phenyl group substituted with one —O—(CH₂)_(m)—W (Wherein W is an ethyl group (in this case m is 0) or a methoxy group (in this case m is 2)), 6-indazolyl, 2-methyl-6-benzothiazolyl, 5-benzothienyl or 2-trifluoromethyl-5-benzimidazolyl.

Preferably n is 0.

Preferably -A-B- is —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH═CH—CH₂— or —CH═CH—, and further preferably —CH₂—CH₂—.

Preferably R⁵ is a hydrogen atom or —(C═O)R⁶.

Preferably R⁶ is a methyl group.

Preferably X¹ or X² is O.

Preferably r is 0 or 2.

Preferably each of Z¹-Z⁴ is a hydrogen atom.

Preferably R¹¹ is a hydrogen atom.

For R¹-R⁴, n and -A-B- in formula (2) in the present invention, groups like the corresponding groups in formula (1) described above are preferred.

As preferred combinations of R¹-R⁴, n and -A-B- in formula (1) in the present invention, in addition to combinations of group(s) included in the above definition for the individual group(s) and group(s) mentioned as preferred example for the individual group(s) and combinations of groups mentioned above as preferred example for the individual groups, there may be mentioned the following 1) to 23).

1) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein the substituent in the optionally substituted phenyl group is a halogen, —CN, an optionally substituted C1-C8 alkyl group or —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted heterocyclic group and m is 0 to 4 or W represents an optionally substituted C1-C8 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH₂—. 2) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted heterocyclic group; n is 0; and -A-B- is —CH₂—CH₂—. 3) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein, the substituent in the optionally substituted phenyl group is a halogen, —CN, an optionally substituted C1-C8 alkyl group or —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted heterocyclic group and m is 0 to 4 or W represents an optionally substituted C1-C8 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH₂—CH₂— or —CH₂—CH₂—CH₂—CH₂—. 4) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted heterocyclic group; n is 0; and -A-B- is —CH₂—CH₂—CH₂— or —CH₂—CH₂—CH₂—CH₂—. 5) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein, the substituent in the optionally substituted phenyl group is a halogen, —CN, an optionally substituted C1-C8 alkyl group or —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted heterocyclic group and m is 0 to 4 or W represents an optionally substituted C1-C8 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH═CH—CH₂— or —CH═CH—. 6) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is an optionally substituted heterocyclic group; n is 0; and -A-B- is —CH₂—CH═CH—CH₂— or —CH═CH—. 7) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted C3-C8 cycloalkyl group; n is 0; and -A-B- is —CH₂—CH₂—. 8) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted C3-C8 cycloalkyl group; n is 0; and -A-B- is —CH₂—CH₂—CH₂— or —CH₂—CH₂—CH₂—CH₂—. 9) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group; R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group or an optionally substituted C3-C8 cycloalkyl group; n is 0; and -A-B- is —CH₂—CH═CH—CH₂— or —CH═CH—. 10) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C3-C8 cycloalkyl group; R⁴ is an optionally substituted phenyl group (wherein the substituent in the optionally substituted phenyl group is a halogen or an optionally substituted C1-C4 alkyl group); n is 0; and -A-B- is —CH₂—CH₂—. 11) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C3-C8 cycloalkyl group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH₂—. 12) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted C3-C8 cycloalkyl group; R⁴ is an optionally substituted heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—. 13) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein the substituent in the optionally substituted phenyl group is a halogen or an optionally substituted C1-C4 alkyl group); n is 0; and -A-B- is —CH₂—CH₂—. 14) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH₂—. 15) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—. 16) In formula (1), R¹ is hydrogen; R² is halogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein the substituent in the optionally substituted phenyl group is a halogen or an optionally substituted C1-C4 alkyl group); n is 0; and -A-B- is —CH₂—CH₂—. 17) In formula (1), R¹ is hydrogen; R² is halogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4); n is 0; and -A-B- is —CH₂—CH₂—. 18) In formula (1), R¹ is hydrogen; R² is halogen; R³ is an optionally substituted saturated heterocyclic group; R⁴ is an optionally substituted heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—. 19) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted piperidyl group or a pyrrolidyl group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4.) or an optionally substituted bicyclic heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—. 20) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an optionally substituted piperidyl group or a pyrrolidyl group; R⁴ is an optionally substituted heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—. 21) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is an unsubstituted piperidyl group or a pyrrolidyl group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4.); n is 0; and -A-B- is —CH₂—CH₂—. 22) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is a cyclohexyl group substituted with an amino group; R⁴ is an optionally substituted phenyl group (wherein the substituent of the optionally substituted phenyl group is —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4 or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4.); n is 0; and -A-B- is —CH₂—CH₂—. 23) In formula (1), R¹ is hydrogen; R² is hydrogen; R³ is a cyclohexyl group substituted with an amino group; R⁴ is an optionally substituted heteroaryl group; n is 0; and -A-B- is —CH₂—CH₂—.

As preferred combinations of R¹-R⁴, n and -A-B- in formula (2) in the present invention, in addition to combinations of group(s) included in the above definition for R¹-R⁴, n and -A-B- in formula (1) and group(s) mentioned above as preferred example for the individual groups and combinations of groups mentioned as preferred example for the individual groups, there may be mentioned the above 1) to 23).

The compound of the present invention may contain a basic group in the molecule. In this case it may be converted to a medically acceptable acid-addition salt if necessary. As such acids, for example, there may be mentioned inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and carbonic acid; and organic acids such as acetic acid, citric acid, malic acid, oxalic acid, tartaric acid, lactic acid, maleic acid, fumaric acid and methanesulfonic acid.

The compound of the present invention may contain an acidic group in the molecule. In this case it may be converted to a medically acceptable salt if necessary. As such salts, there may be mentioned salts with non-toxic cations. Specifically, there may be mentioned salts with alkali metal ions such as Na⁺ and K⁺, alkaline earth metal ions such as Mg²⁺ and Ca²⁺, metal ions such as Al³⁺ and Zn²⁺, ammonium ion, and organic bases such as triethylamine, ethylenediamine, propanediamine, pyrrolidine, piperidine, piperazine, pyridine, lysine, choline, ethanolamine, N,N-dimethylethanolamine, 4-hydroxypiperidine, glucosamine and N-methylglucamine.

When the compound of the present invention exists enantiomer, the present invention includes racemic and optically active forms. When the compound of the present invention contains two or more chiral carbon atoms, the present invention includes all diastereomers. When the compound of the present invention exists trans- cis geometrical isomer, the present invention includes either the trans form or the cis form.

As examples of compound represented by formula (1) in the present invention, there may be mentioned compounds listed in Tables A to G.

TABLE A

Compound No. R¹ R² R³ R⁴ n Z A-001 H H

0 H A-002 H H

0 H A-003 H H

0 H A-004 H H

0 H A-005 H H

0 H A-006 H H

1 H A-007 H H

0 H A-008 H H

0 H A-009 H H

0 H A-010 H H

0 H A-011 H H

0 H A-012 H H

0 H A-013 H H

0 H A-014 H H

1 H A-015 H H

1 H A-016 H H

1 H A-017 H H

1 H A-018 H F

0 H A-019 F F

0 H A-020 H H OH

0 H A-021 H H

0 H A-022 H H

0 H A-023 H H

0 H A-024 H H

0

A-025 H H

0 H A-026 H H

0 H A-027 H H

0 H A-028 H H

0 H A-029 H H

0 H A-030 H H

0 H A-031 H H

0 H A-032 H H

0 H A-033 H H

0 H A-034 H H

0 H A-035 H H

0 H A-036 H H

0 H A-037 H H

0 H A-038 H H

0 H A-039 H H

0 H A-040 H H

0 H A-041 H H

0 H A-042 H H

0 H A-043 H H

0 H A-044 H H

0 H A-045 H H

0 H A-046 H H

0 H A-047 H H

0 H A-048 H H

0 H A-049 H H

0 H A-050 H H

0 H A-051 H H

0 H A-052 H H

0 H A-053 H H

0 H A-054 H H

0 H A-055 H H

0 H A-056 H H

0 H A-057 H H

0 H A-058 H H

0 H A-059 H H

0 H A-060 H H

0 H A-061 H H

0 H A-062 H H

0 H A-063 H H

0 H A-064 H H

0 H A-065 H H

0 H A-066 H H

0 H A-067 H H

0 H A-068 H H

0 H A-069 H H

0 H A-070 H H

0 H A-071 H H

0 H A-072 H H

0 H A-073 H H

0 H A-074 H H

0 H A-075 H H

0 H A-076 H H

0 H A-077 H H

0 H A-078 H H

0 H A-079 H H

0 H A-080 H H

0 H A-081 H H

0 H A-082 H H

0 H A-083 H H

0 H A-084 H H

0 H A-085 H H

0 H A-086 H H

0 H A-087 H H

0 H A-088 H H

0 H A-089 H H

0 H A-090 H H

0 H A-091 H H

0 H A-092 H H

H 0 H A-093 H H

H 0 H A-094 H H

H 0 H A-095 H H

0 H A-096 H H

Me 0 H A-097 H H

0 H A-098 H H

0 H A-099 H H

0 H A-100 H H

0 H A-101 H Cl

0 H A-102 H Br

0 H

TABLE B

Compound No. R¹ R² R³ R⁴ n B-001 H H

B-002 H H

0 B-003 H H

0 B-004 H H

0 B-005 H H

0 B-006 H H

0 B-007 H H

0 B-008 H H

1 B-009 H H

0 B-010 H H

0 B-011 H H

0 B-012 H H

0 B-013 H H

0 B-014 H H

0 B-015 H H

1 B-016 H H

0 B-017 H H

0 B-018 H H

1 B-019 H H

1 B-020 H H

1 B-021 H H

0 B-022 H H

0 B-023 H H

0 B-024 H H

0 B-025 H H

0 B-026 H H

1 B-027 H H

1 B-028 H H

1 B-029 H F

0 B-030 F F

0 B-031 H H

0 B-032 H H

0 B-033 H H

0 B-034 H H

0 B-035 H H

0 B-036 H H

0 B-037 H H

0 B-038 H H

0 B-039 H H

0 B-040 H H

0 B-041 H H

0 B-042 H H

0 B-043 H H

0 B-044 H H

0 B-045 H H

0 B-046 H H

0 B-047 H H

0 B-048 H H

0 B-049 H H

0 B-050 H H

0 B-051 H H

0 B-052 H H

0 B-053 H H

0 B-054 H H

0 B-055 H H

0 B-056 H H

0 B-057 H H

0 B-058 H H

0 B-059 H H

0 B-060 H H

0 B-061 H H

0 B-062 H H

0 B-063 H H

0 B-064 H H

0 B-065 H H

0 B-066 H H

0 B-067 H H

0 B-068 H H

0 B-069 H H

0 B-070 H H

0 B-071 H H

0 B-072 H H

0 B-073 H H

0 B-074 H H

0 B-075 H H

0 B-076 H H

0 B-077 H H

0 B-078 H H

0 B-079 H H

0 B-080 H H

0 B-081 H H

0 B-082 H H

0 B-083 H H

0 B-084 H H

0 B-085 H H

0 B-086 H H

0 B-087 H H

0 B-088 H H

0 B-089 H H

0 B-090 H H

0 B-091 H H

0 B-092 H H

0 B-093 H H

0 B-094 H H

0 B-095 H H

0 B-096 H H

0 B-097 H H

0 B-098 H H

H 0 B-099 H H

H 0 B-100 H H

H 0

TABLE C

Compound No. R¹ R² R³ R⁴ n C-001 H H

0 C-002 H H

0 C-003 H H

0 C-004 H H

0 C-005 H H

0 C-006 H H

1 C-007 H H

0 C-008 H H

0 C-009 H H

0 C-010 H H

0 C-011 H H

0 C-012 H H

0 C-013 H H

0 C-014 H H

1 C-015 H H

1 C-016 H H

1 C-017 H H

1 C-018 H F

0 C-019 F F

0 C-020 H H

0 C-021 H H

0 C-022 H H

0 C-023 H H

0 C-024 H H

0 C-025 H H

0 C-026 H H

0 C-027 H H

0 C-028 H H

0 C-029 H H

0 C-030 H H

0 C-031 H H

0 C-032 H H

0 C-033 H H

0 C-034 H H

0 C-035 H H

0 C-036 H H

0 C-037 H H

0 C-038 H H

0 C-039 H H

0 C-040 H H

0 C-041 H H

0 C-042 H H

0 C-043 H H

0 C-044 H H

0 C-045 H H

0 C-046 H H

0 C-047 H H

0 C-048 H H

0 C-049 H H

0 C-050 H H

0 C-051 H H

0 C-052 H H

0 C-053 H H

0 C-054 H H

0 C-055 H H

0 C-056 H H

0 C-057 H H

0 C-058 H H

0 C-059 H H

0 C-060 H H

0 C-061 H H

0 C-062 H H

0 C-063 H H

0 C-064 H H

0 C-065 H H

0 C-066 H H

0 C-067 H H

0 C-068 H H

0 C-069 H H

0 C-070 H H

0 C-071 H H

0 0-072 H H

0 C-073 H H

0 C-074 H H

0 C-075 H H

0 C-076 H H

0 C-077 H H

0 C-078 H H

0 C-079 H H

0 C-080 H H

0 C-081 H H

0 C-082 H H

0 C-083 H H

0 C-084 H H

0 C-085 H H

0 C-086 H H

0

TABLE D

Compound No. R¹ R² R³ R⁴ n D-001 H H

0 D-002 H H

1 D-003 H H

0 D-004 H H

0 D-005 H H

1 D-006 H H

0 D-007 H H

0 D-008 H H

0 D-009 H H

0 D-010 H H

1 D-011 H H

0 D-012 H H

0 D-013 H H

0 D-014 H H

0 D-015 H H

0 D-016 H H

1 D-017 H H

1 D-018 H F

0 D-019 F F

0 D-020 H H

0 D-021 H H

0 D-022 H H

0 D-023 H H

0 D-024 H H

0 D-025 H H

0 D-026 H H

0 D-027 H H

0 D-028 H H

0 D-029 H H

0 D-030 H H

0 D-031 H H

0 D-032 H H

0 D-033 H H

0 D-034 H H

0 D-035 H H

0 D-036 H H

0 D-037 H H

0 D-038 H H

0 D-039 H H

0 D-040 H H

0 D-041 H H

0 D-042 H H

0 D-043 H H

0 D-044 H H

0 D-045 H H

0 D-046 H H

0 D-047 H H

0 D-048 H H

0 D-049 H H

0 D-050 H H

0 D-051 H H

0 D-052 H H

0 D-053 H H

0 D-054 H H

0 D-055 H H

0 D-056 H H

0 D-057 H H

0 D-058 H H

0 D-059 H H

0 D-060 H H

0 D-061 H H

0 D-062 H H

0 D-063 H H

0 D-064 H H

0 D-065 H H

0 D-066 H H

0 D-067 H H

0 D-068 H H

0 D-069 H H

0 D-070 H H

0 D-071 H H

0 D-072 H H

0 D-073 H H

0 D-074 H H

0 D-075 H H

0 D-076 H H

0 D-077 H H

0 D-078 H H

0 D-079 H H

0 D-080 H H

0 D-081 H H

0 D-082 H H

0 D-083 H H

0 D-084 H H

0 D-085 H H

0

TABLE E

Compound No. R¹ R² R³ R⁴ n E-001 H H

0 E-002 H H

0 E-003 H H

0 E-004 H H

0 E-005 H H

0 E-006 H H

1 E-007 H H

0 E-008 H H

0 E-009 H H

0 E-010 H H

0 E-011 H H

0 E-012 H H

0 E-013 H H

0 E-014 H H

1 E-015 H H

1 E-016 H H

1 E-017 H H

1 E-018 H F

0 E-019 F F

0 E-020 H H

0 E-021 H H

0 E-022 H H

0 E-023 H H

0 E-024 H H

0 E-025 H H

0 E-026 H H

0 E-027 H H

0 E-028 H H

0 E-029 H H

0 E-030 H H

0 E-031 H H

0 E-032 H H

0 E-033 H H

0 E-034 H H

0 E-035 H H

0 E-036 H H

0 E-037 H H

0 E-038 H H

0 E-039 H H

0 E-040 H H

0 E-041 H H

0 E-042 H H

0 E-043 H H

0 E-044 H H

0 E-045 H H

0 E-046 H H

0 E-047 H H

0 E-048 H H

0 E-049 H H

0 E-050 H H

0 E-051 H H

0 E-052 H H

0 E-053 H H

0 E-054 H H

0 E-055 H H

0 E-056 H H

0 E-057 H H

0 E-058 H H

0 E-059 H H

0 E-060 H H

0 E-061 H H

0 E-062 H H

0 E-063 H H

0 E-064 H H

0 E-065 H H

0 E-066 H H

0 E-067 H H

0 E-068 H H

0 E-069 H H

0 E-070 H H

0 E-071 H H

0 E-072 H H

0 E-073 H H

0 E-074 H H

0 E-075 H H

0 E-076 H H

0 E-077 H H

0 E-078 H H

0 E-079 H H

0 E-080 H H

0 E-081 H H

0 E-082 H H

0 E-083 H H

0 E-084 H H

0 E-085 H H

0

TABLE F

Compound No. R¹ R² R³ R⁴ n Z F-001 H H

0 H F-002 H H

0

F-003 H H

0 H F-004 H H

0 H F-005 H H

0 H F-006 H H

0 H F-007 H H

1 H F-008 H H

0 H F-009 H H

0 H F-010 H H

0 H F-011 H H

0 H F-012 H H

0 H F-013 H H

0 H F-014 H H

0 H F-015 H H

1 H F-016 H H

1 H F-017 H H

1 H F-018 H H

1 H F-019 H F

0 H F-020 F F

0 H F-021 H H

0 H F-022 H H

0 H F-023 H H

0 H F-024 H H

0 H F-025 H H

0 H F-026 H H

0 H F-027 H H

0 H F-028 H H

0 H F-029 H H

0 H F-030 H H

0 H F-031 H H

0 H F-032 H H

0 H F-033 H H

0 H F-034 H H

0 H F-035 H H

0 H F-036 H H

0 H F-037 H H

0 H F-038 H H

0 H F-039 H H

0 H F-040 H H

0 H F-041 H H

0 H F-042 H H

0 H F-043 H H

0 H F-044 H H

0 H F-045 H H

0 H F-046 H H

0 H F-047 H H

0 H F-048 H H

0 H F-049 H H

0 H F-050 H H

0 H F-051 H H

0 H F-052 H H

0 H F-053 H H

0 H F-054 H H

0 H F-055 H H

0 H F-056 H H

0 H F-057 H H

0 H F-058 H H

0 H F-059 H H

0 H F-060 H H

0 H F-061 H H

0 H F-062 H H

0 H F-063 H H

0 H F-064 H H

0 H F-065 H H

0 H F-066 H H

0 H F-067 H H

0 H F-068 H H

0 H F-069 H H

0 H F-070 H H

0 H F-071 H H

0 H F-072 H H

0 H F-073 H H

0 H F-074 H H

0 H F-075 H H

0 H F-076 H H

0 H F-077 H H

0 H F-078 H H

0 H F-079 H H

0 H F-080 H H

0 H F-081 H H

0 H F-082 H H

0 H F-083 H H

0 H F-084 H H

0 H F-085 H H

0 H F-086 H H

0 H F-87  H H

0 H F-88  H H

0 H F-89  H H

0 H F-90  H H

0 H

TABLE G

Compound No. R¹ R² R³ R⁴ n G-001 H H

0 G-002 H H

0 G-003 H H

0 G-004 H H

0 G-005 H H

0 G-006 H H

1 G-007 H H

0 G-008 H H

0 G-009 H H

0 G-010 H H

0 G-011 H H

0 G-012 H H

0 G-013 H H

0 G-014 H H

1 G-015 H H

1 G-016 H H

1 G-017 H H

1 G-018 H F

0 G-019 F F

0 G-020 H H

0 G-021 H H

0 G-022 H H

0 G-023 H H

0 G-024 H H

0 G-025 H H

0 G-026 H H

0 G-027 H H

0 G-028 H H

0 G-029 H H

0 G-030 H H

0 G-031 H H

0 G-032 H H

0 G-033 H H

0 G-034 H H

0 G-035 H H

0 G-036 H H

0 G-037 H H

0 G-038 H H

0 G-039 H H

0 G-040 H H

0 G-041 H H

0 G-042 H H

0 G-043 H H

0 G-044 H H

0 G-045 H H

0 G-046 H H

0 G-047 H H

0 G-048 H H

0 G-049 H H

0 G-050 H H

0 G-051 H H

0 G-052 H H

0 G-053 H H

0 G-054 H H

0 G-055 H H

0 G-056 H H

0 G-057 H H

0 G-058 H H

0 G-059 H H

0 G-060 H H

0 G-061 H H

0 G-062 H H

0 G-063 H H

0 G-064 H H

0 G-065 H H

0 G-066 H H

0 G-067 H H

0 G-068 H H

0 G-069 H H

0 G-070 H H

0 G-071 H H

0 G-072 H H

0 G-073 H H

0 G-074 H H

0 G-075 H H

0 G-076 H H

0 G-077 H H

0 G-078 H H

0 G-079 H H

0 G-080 H H

0 G-081 H H

0 G-082 H H

0 G-083 H H

0 G-084 H H

0 G-085 H H

0 G-086 H H

H 0 G-087 H H

Me 0 G-88  H H

H 0 G-089 H H

H 0

The pyrazolopyrimidine derivative represented by the above formula (1) exists in tautomeric forms exemplified by the following formula.

(In the formula, R¹, R², R³, R⁴, n and -A-B- are as defined for formula (1)).

These tautomers are also included in the scope of the present invention.

As examples of compound represented by formula (2) in the present invention, there may be mentioned compounds having R¹, R², R³, R⁴, n and -A-B- listed in Tables A to G.

The compounds of the present invention can be synthesized by the following method. In each formula, R¹-R⁴, -A-B- and n are as defined in the above formula (1). Reagents and solvents shown as conditions in chemical formulae are examples, as mentioned in the text. Each of abbreviations of substituents, reagents and solvents in the text and tables represent the following.

Me: methyl Et: ethyl ^(i)Pr: isopropyl ^(t)Bu: tert-butyl Cy: cyclohexyl Ms: methanesulfonyl Boc: tert-butoxycarbonyl TBS: tert-butyldimethylsilyl TBAF: tetrabutylammonium fluoride TFA: trifluoroacetic acid HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate Dess-Martin periodinane: 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one

DMAP: 4-N,N-dimethylaminopyridine NMO: N-methylmorpholine-N-oxide DMF: N,N-dimethylformamide

THF: tetrahydrofuran PTLC: preparative thin layer chromatography Grubbs reagent: benzylidene-bis(tricyclohexylphosphine)dichlororuthenium

NBS: N-bromosuccinimide NCS: N-chlorosuccinimide

1) The compound represented by formula (4) can be obtained by reaction of the compound represented by formula (3) and allylmalonic diester in an appropriate organic solvent (for example, ethanol or methanol) under a condition from room temperature to heating under reflux in the presence of a base (for example, sodium ethoxide or sodium methoxide). (References: J. Med. Chem., 1976, 19, 296 and J. Med. Chem., 1977, 20, 296) 2) The compound represented by formula (5) can be obtained by reaction of the compound represented by formula (4) and a halogenating agent (for example, phosphoryl chloride) either in an appropriate organic solvent (for example, acetonitrile) or without solvent under a condition from room temperature to heating under reflux in the presence or absence of an appropriate base (for example, dimethylaniline).

3) The compound represented by formula (6) or (15) can be obtained by reaction of the compound represented by formula (5) or (14), respectively, with an oxidizing agent (for example, sodium periodate and osmium tetraoxide) in an appropriate solvent (for example, THF-water mixed solvent) at a temperature ranging from 0° C. to room temperature. 4) The compound represented by formula (7) or (16) can be obtained by reaction of the compound represented by formula (6) or (15), respectively, with a reducing agent (for example, sodium borohydride) in an appropriate organic solvent (for example, ethanol or methanol) at a temperature ranging from 0° C. to 40° C. 5) The compound represented by formula (8) or (18) can be obtained by reaction of the compound represented by formula (5) or (14), respectively, with a borane agent (for example, borane-dimethylsulfide complex) in an appropriate organic solvent (for example, THF) at a temperature ranging from 0° C. to room temperature followed by reaction with aqueous hydrogen peroxide in aqueous sodium hydroxide solution. 6) The compound represented by formula (10), (17), (19) or (42) can be obtained by reaction of the compound represented by formula (9), (16), (18) or (41), respectively, with tert-butylchlorodimethylsilane in an appropriate organic solvent (for example, methylene chloride or DMF) at a temperature ranging from 0° C. to 40° C. in the presence of a base (for example, triethylamine or imidazole). (Reference: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.)

7) The compound represented by formula (11) or (13) can be obtained by reaction of the compound represented by formula (10) or (5), respectively, with an amine compound represented as R⁴NH₂ in an appropriate organic solvent (for example, 2-propanol, DMF, THF or DMF-THF mixed solvent) under a condition from room temperature to heating under reflux in the presence of a base (for example triethylamine or sodium hydride). 8) The compound represented by formula (41) can be obtained by reaction of the compound represented by formula (14) with an oxidizing agent (for example, osmium tetraoxide and N-methylmorpholine-N-oxide) in an appropriate solvent (for example, acetone-water mixed solvent) at a temperature ranging from 0° C. to room temperature. (References: Tetrahedron Lett., 1973 (1976) and Org. Synth. Collective volume 6, 342) 9) The compound represented by formula (12) or (14) can be obtained by reaction of the compound represented by formula (11) or (13), respectively, with di-tert-butyl dicarbonate in an appropriate organic solvent (for example, 1,4-dioxane) under a condition from room temperature to heating under reflux in the presence of a base (for example triethylamine or 4-N,N-dimethylaminopyridine). (Reference: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.) 10) The compound represented by formula (25) or (27) can be obtained by reaction of the compound represented by formula (15) or (26), respectively, with an oxidizing agent (for example, sodium chlorite in the presence of 2-methyl-2-butene and sodium dihydrogenphosphate) in an appropriate solvent (for example, tert-butanol-water mixed solvent) at a temperature ranging from 0° C. to room temperature.

11) The compound represented by formula (26) can be obtained by reaction of the compound represented by formula (18) with an oxidizing agent [for example, Dess-Martin periodinane, i.e., 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one] in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to room temperature. (References: J. Org. Chem., 48, 4155 (1983); J. Am. Chem. Soc., 113, 7277 (1991)) 12) The compound represented by formula (20), (32) or (43) can be obtained by reaction of the compound represented by formula (12), (14) or (42), respectively, with an amine represented by formula R³—(CH₂)_(n)—NH₂ in an appropriate organic solvent (for example, acetonitrile) or without solvent under a condition from room temperature to heating under reflux. (When R³ in the compound represented by formula R³—(CH₂)_(n)—NH₂ contains an unprotected primary amino group, the compound represented by formula (12), (14) or (42) is reacted with R³—(CH₂)_(n)—NH₂ by the above-mentioned method and then the amino group in R³ moiety is protected by treatment with di-tert-butyl dicarbonate in an appropriate organic solvent (for example, 1,4-dioxane or methylene chloride) under a condition from room temperature to heating under reflux in the presence of bases (for example, triethylamine and 4-N,N-dimethylaminopyridine) to obtain the corresponding tert-butoxycarbonyl-protected compound, which is defined as the compound represented by formula (20), (32) or (43), respectively.)

13) The compound represented by formula (21) can be obtained by reaction of the compound represented by formula (20) with a fluoride ion agent (for example, n-tetrabutylammonium fluoride) in an appropriate organic solvent (for example, THF) at a temperature ranging from 0° C. to room temperature. (Reference: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.) 14) The compound represented by formula (22) or (46) can be obtained by reaction of the compound represented by formula (21) or (43), respectively, with a mesylating agent (for example, methanesulfonyl chloride) in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to room temperature in the presence of a base (for example, triethylamine). (Reference: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.)

15) The compound represented by formula (23) or (47) can be obtained by reaction of the compound represented by formula (22) or (46), respectively, with a base (for example, sodium hydride) in an appropriate organic solvent (for example, DMF, THF or DMF-THF mixed solvent) at a temperature ranging from 0° C. to 60° C. 16) The compound represented by formula (29) can be obtained by reaction of the compound represented by formula (28) with an amine compound represented by formula R³—(CH₂)_(n)—NH₂ in an appropriate organic solvent (for example, DMF) at a temperature ranging from 0° C. to 40° C. in the presence of a peptide condensing agent [for example, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate] and a base (for example, diisopropyethylamine).

17) The compound represented by formula (30) can be obtained by reaction of the compound represented by formula (29) with a base (for example, sodium hydride) in an appropriate organic solvent (for example, DMF, THF or DMF-THF mixed solvent) at a temperature ranging from 0° C. to 60° C. 18) The compound represented by formula (38) can be obtained by reaction of the compound represented by formula (15) with hydroxylamine in the presence of a reducing agent (for example, sodium cyanoborohydride) in an appropriate organic solvent (for example, methanol or ethanol) under a condition from 0° C. to heating under reflux.

19) The compound represented by formula (40) can be obtained by reaction of the compound represented by formula (39) with an appropriate reagent (for example, acetic anhydride) in the presence of a base (for example, triethylamine) in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to 40° C. 20) The compound represented by formula (33) can be obtained by reaction of the compound represented by formula (32) with an allylating agent (for example, allyl bromide) in the presence of a base (for example, sodium hydride) in an appropriate organic solvent (for example, DMF, THF or DMF-THF mixed solvent) at a temperature ranging from 0° C. to 70° C. 21) The compound represented by formula (34) can be obtained by reaction of the compound represented by formula (33) with an olefin metathesis catalyst [for example, Grubbs catalyst, i.e., benzylidenebis(tricyclohexylphosphine)dichlororuthenium] in an appropriate organic solvent (for example, toluene) at a temperature ranging from 0° C. to 40° C. (Reference: Angew. Chem. Int. Ed., 2002, 41, 176) 22) The compound represented by formula (36) can be obtained by reaction of the compound represented by formula (34) with hydrogen in the presence of a palladium catalyst (for example, palladium-carbon) in an appropriate organic solvent (for example, methanol, ethanol or 1,4-dioxane-ethanol mixed solvent) at room temperature.

23) The compound represented by formula (44) can be obtained by reaction of the compound represented by formula (43) with an oxidizing agent [for example, Dess-Martin periodinane, i.e., 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one] in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to 40° C.

24) Each compound represented by formula (49) can be obtained by reaction of the corresponding compound represented by formula (32) with an oxidizing agent (for example, sodium periodate and osmium tetraoxide) in an appropriate solvent (for example, THF-water mixed solvent) at a temperature ranging from 0° C. to 40° C.

25) The compound represented by formula (52) or (53) can be obtained by reaction of the compound represented by formula (51) with a nucleophilic halogenatigen agent (for example, 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate), N-bromosuccinimide, or N-chlorosucciminde) in an appropriate organic solvent (for example, DMF, methylene chloride, or THF) at a temperature ranging from 0° C. to 40° C. (Reference: J. Chem. Soc. Perkin 1, 1996, 2069.)

26) The compound represented by formula (1) can be obtained by reaction of the compound represented by formula (2) with an acid (for example, trifluoroacetic acid) in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to room temperature. (Reference: Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons Inc.)

27) The compound represented by formula (45) or (48) can be obtained by reaction of the compound represented by formula (44) or (47), respectively, with an acid (for example, trifluoroacetic acid) in an appropriate organic solvent (for example, methylene chloride) at a temperature ranging from 0° C. to room temperature.

A preparation comprising the compound of the present invention or a medically acceptable salt thereof as an active ingredient is prepared by using carriers, excipients or other additives usually used for formulation. As carriers and excipients used for formulation, either solid or liquid may be used, and for example, there may be mentioned lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cacao butter, ethylene glycol and others conventionally used. The preparation may be administrated either orally as tablets, pills, capsules, granule, powder, liquid or the like or parenterally through injection such as an intravenous injection and an intramuscular injection, suppository, percutaneous administration or the like.

As diseases for which the MAPKAP-K2 inhibitor of the present invention is effective, there may be mentioned neurodegenerative/neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD).

As autoimmune diseases, specifically, there may be mentioned rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, graft-versus-host disease, diabetes mellitus or Crohn's disease.

The dose of the compound of the present invention is, although it varies depending on the kind of disease, the administration route, the age and sex of patient and the degree of disease, usually 1-500 mg/day for one adult.

EXAMPLES

The present invention will be explained with specific examples, although the present invention is not limited to these examples.

The compound number of each compound in the following examples corresponds to the compound number given to the compound mentioned as preferred example in Tables A to G. The structures of novel compounds isolated were confirmed by ¹H NMR and/or mass analysis measured on a single quadrupole instrumentation equipped with an electrospray source or other appropriate analytical methods.

For ¹H NMR spectra (400 MHz, DMSO-d₆ or CDCl₃), chemical shifts (δ: ppm) and coupling constants (J: Hz) are shown. For results of mass analysis, M+H, that is, the measured value observed as the molecular mass of compound (M) with one proton (H) added, is shown. “HPLC retention time” represents the retention time (unit: min) of compound in HPLC analysis under the following analytical conditions.

Conditions for HPLC (High performance liquid chromatography) Instrumental system: Hewlett-Packard 1100HPLC Column: Cadenza CD-C18 (Intact) 100 mm×4.6 mm (i.d.)

Column Temperature: 40° C.

[HPLC condition A] Solvent: A: H₂O/acetonitrile=95/5, 0.05% TFA (trifluoroacetic acid)

B: H₂O/acetonitrile=5/95, 0.05% TFA (trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0 to 1 min; Solvent B: 10%, Solvent A: 90% 1 to 13 min; Solvent B: 10% to 70%, Solvent A: 90% to 30% 13 to 14 min; Solvent B: 70% to 100%, Solvent A: 30% to 0% 14 to 16 min; Solvent B: 100%, Solvent A: 0% 16 to 19 min; Solvent B: 100% to 10%, Solvent A: 0% to 90% [HPLC condition B] Solvent: A: H₂O/acetonitrile=95/5, 0.05% TFA (trifluoroacetic acid)

B: H₂O/acetonitrile=5/95, 0.05% TFA (trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0 to 1 min; Solvent B: 1%, Solvent A: 99% 1 to 13 min; Solvent B: 1% to 55%, Solvent A: 99% to 45% 13 to 14 min; Solvent B: 55% to 100%, Solvent A: 45% to 0% 14 to 16 min; Solvent B: 100%, Solvent A: 0% 16 to 19 min; Solvent B: 100% to 1%, Solvent A: 0% to 99%

Reference Example 1 Synthesis of 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine

To an ethanolic solution (0.2 L) containing sodium ethoxide (7.8 g, 0.11 mol), 3-aminopyrazole (5.0 g, 0.6 mol) and diethyl allylmalonate (12 mL, 0.61 mol) were added at room temperature. The resultant mixture was heated under reflux for 24 hr. After the mixture was cooled down to room temperature, the solvent was distilled off. The residue was dissolved in water (150 mL) and the aqueous solution was washed with ethyl acetate. This aqueous layer was acidified by adding 6 mol/L hydrochloric acid, and the resultant precipitate was collected by filtration and dried under reduced pressure to obtain 6-allyl-5,7-dihydroxypyrazolo[1,5-a]pyrimidine (9.3 g).

The above dihydroxy compound was suspended in phosphoryl chloride (0.21 kg). After this suspension was stirred at 120° C. for 5 hr, the excessive phosphoryl chloride was distilled off. The residue was neutralized by adding aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (5.2 g, yield 40% in two steps).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.19 (d, J=2.2 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 5.98-5.88 (m, 1H), 5.20-5.13 (m, 2H), 3.72 (dt, J=6.1 and 1.6 Hz, 2H).

Reference Example 2 Synthesis of 2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol

To a mixed solution of THF (24 mL) and water (6 mL) containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (1.82 g, 7.89 mmol), sodium periodate (5.12 g, 23.9 mmol) and osmium tetraoxide (2.5 w/v % in tert-butanol, 3 mL, 0.23 mmol) were added with ice-cooling. After this mixture was stirred at room temperature for 3 hr, aqueous sodium sulfite was added here. The resultant mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain 5,7-dichloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidine.

The above aldehyde (1.82 mmol) was dissolved in methanol (27 mL), and sodium borohydride (302 mg, 7.98 mmol) was added to this solution with ice-cooling. After this mixture was stirred for 30 min, aqueous ammonium chloride was added here. The resultant mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off, and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (617 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.17 (d, J=2.2 Hz, 1H), 6.70 (d, J=1.9 Hz, 1H), 3.90 (t, 2H), 3.21 (t, 2H).

Reference Example 3 Synthesis of 6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyrimidine

To a methylene chloride (50 mL) solution containing 2-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)ethanol (640 mg, 2.77 mmol), triethylamine (3.86 mL, 27.7 mmol) and tert-butylchlorodimethylsilane (1.25 g, 8.31 mmol) were added, and this mixture was stirred at room temperature for 16 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (1.04 g).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.17 (s, J=2.4 Hz, 1H), 6.70 (d, J=2.2 Hz, 1H), 3.91 (dd, J=13.2 and 6.3 Hz, 2H), 3.24-3.19 (m, 2H), 0.84 (s, 9H), 0.00 (s, 6H).

Reference Example 4 Synthesis of 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol

To a tetrahydrofuran (85 mL) solution containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.8 g, 25 mmol), borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution, 20 mL, 41 mmol) was added with ice-cooling over 30 min. This mixture was stirred at room temperature for 1 hr and again cooled on ice. Here, aqueous sodium hydroxide (1 mol/L, 40 mL) was added over 20 min, and hydrogen peroxide (30% aqueous solution, 3 mL) was further added, and the mixture was stirred for 1 hr. After the reaction, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (25 to 50% ethyl acetate-hexane) to obtain the title compound (3.4 g, yield 31%).

Reference Example 5 Synthesis of {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]amine

To an isopropanol (3.0 mL) solution containing 6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5,7-dichloropyrazolo[1,5-a]pyrimidine (512 mg, 1.49 mmol), triethylamine (836 μL, 5.96 mmol) and 4-(2-methoxyethoxy)phenylamine (299 mg, 1.79 mmol) were added, and this mixture was heated at 85° C. with stirring. After the reaction, the solvent was concentrated, sodium hydrogen carbonate was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.

Reference Example 6 Synthesis of tert-butyl {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate

To a 1,4-dioxane (7.0 mL) solution containing {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]amine (570 mg, 1.20 mmol), di-tert-butyl dicarbonate (515 μL, 2.24 mmol) and N,N-dimethylaminopyridine (35.2 mg, 0.29 mmol) were added, and this mixture was stirred with heating at 40° C. After the reaction, the solvent was concentrated, sodium hydrogen carbonate was added here, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the residue, which was used for the subsequent reaction without purification.

Reference Example 7 Synthesis of tert-butyl (S)-3-{7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate

To an acetonitrile (5 mL) solution containing tert-butyl {6-[2-(tert-butyldimethylsilanyloxy)ethyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}[4-(2-methoxyethoxy)phenyl]carbamate (570 mg, 1.20 mmol), (S)-3-amino-1-tert-butoxycarbonylpiperidine (1.51 g) was added, and this mixture was stirred at 85° C. for 48 hr. The reaction solution was concentrated, and the residue was purified with column chromatography (35% ethyl acetate-hexane) to obtain the title compound (204 mg).

Reference Example 8 Synthesis of tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

To a tetrahydrofuran (5 mL) solution containing tert-butyl (S)-3-{7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (193 mg, 0.261 mmol), tetrabutylammonium fluoride (474 μL, 0.474 mmol) was added, and this mixture was stirred at room temperature for 1.5 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (233 mg).

Reference Example 9 Synthesis of tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-methanesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

To a methylene chloride (5 mL) solution containing tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (216 mg, 0.345 mmol), triethylamine (480 μL, 3.45 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added, and this mixture was stirred at room temperature for 30 min. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (258 mg).

Reference Example 10 Synthesis of tert-butyl {5-(4-tert-butoxycarbonylaminocyclohexylamino)-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-7-yl}-(4-ethoxyphenyl)carbamate

To a methylene chloride solution (0.5 mL) of tert-butyl {5-(4-aminocyclohexylamino)-6-[2-(tert-butyldimethylsilanyloxy)ethyl]pyrazolo[1,5-a]pyrimidin-7-yl}-(4-ethoxyphenyl)carbamate (50 mg, 0.08 mmol), triethylamine (33 μL, 0.24 mmol), di-tert-butyl dicarbonate (32 mg, 0.16 mmol) and 4-N,N-dimethylaminopyridine (2 mg, 0.02 mmol) were added and the mixture was stirred at room temperature. After the reaction, aqueous ammonium chloride solution was added to the reaction solution and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated to obtain the title compound.

Example 1 Synthesis of tert-butyl (S)-3-(8-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate

To a mixed solution of tetrahydrofuran (5 mL) and N,N-dimethylformamide (1.8 mL) containing tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-methanesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (162 mg, 0.231 mmol), sodium hydride (with 40% mineral oil added) (22 mg, 0.55 mmol) was added, and this mixture was stirred at room temperature for 30 min. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound.

HPLC retention time (HPLC condition A): 15.42 min

ESI/MS: 610.15 (M+H, C₃₂H₄₄N₆O₈)

Example 2 Synthesis of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

The title compound was synthesized using tert-butyl (S)-3-[7-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6-(2-methanesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate by the same method as Example 1.

HPLC retention time (HPLC condition A): 15.55 min

ESI/MS: 606.10 (M+H, C₃₁H₃₉N₇O₄S₁)

Reference Example 11 Synthesis of (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)amine

To an isopropanol (52 mL) solution containing 6-allyl-5,7-dichloropyrazolo[1,5-a]pyrimidine (5.98 g), triethylamine (12.7 mL) and phenetidine (4.30 g) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off. Saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (8.62 g).

Reference Example 12 Synthesis of 3-[5-chloro-7-(4-ethoxyphenylamino)pyrazolo[1,5-a]pyrimidin-6-yl]propan-1-ol

To an isopropanol (3 mL) solution containing 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-6-yl)propan-1-ol (224 mg, 0.910 mmol), triethylamine (253 μL, 1.82 mmol) and phenethidine (128 μL, 1.00 mmol) were added, and this mixture was stirred at 40° C. for 5 hr. After the reaction, the solvent was distilled off, aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (212 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.17 (s, 1H), 7.98 (d, J=2.2 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.48 (d, J=2.2 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.33 (t, J=6.3 Hz, 2H), 2.49 (m, 2H), 1.59 (m, 2H), 1.44 (t, J=7.1 Hz, 2H).

Reference Example 13 Synthesis of {6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}(4-ethoxyphenyl)amine

To a methylene chloride (14 mL) solution containing [6-(3-hydroxypropyl)-5-chloropyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)amine (1.43 g, 4.12 mmol), triethylamine (861 μL, 6.18 mmol) and tert-butylchlorodimethylsilane (808 mg, 5.36 mmol) were added with ice-cooling, and this mixture was stirred at room temperature for 16 hr. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated and the residue was purified with column chromatography (10 to 15% ethyl acetate-hexane) to obtain the title compound (2.03 g, yield 100%).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.08 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.47 (d, J=2.4 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.30 (t, J=6.3 Hz, 2H), 2.45 (m, 2H), 1.56 (s, 9H), 1.55 (m, 2H), 1.44 (t, J=7.1 Hz, 3H), 0.84 (s, 9H), −0.03 (s, 9H).

Reference Example 14 Synthesis of tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl) (4-ethoxyphenyl)carbamate

To a 1,4-dioxane (130 mL) solution containing (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)amine (8.62 g), di-tert-butoxycarboxylate (11.4 g) and N,N-dimethylaminopyridine (0.80 g) were added, and this mixture was stirred at room temperature for 2 hr. After the reaction, the solvent was distilled off, and the residue was purified with column chromatography (10% ethyl acetate-hexane) to obtain the title compound (10.49 g, yield 93%).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.16 (s, 1H), 7.18 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.9 Hz, 2H), 6.69 (d, J=2.2 Hz, 1H), 5.64 (s, 1H), 5.00 (td, J=15.4 and 4.2 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.44 (m, 2H), 1.39 (t, J=7.1 Hz, 3H), 1.26 (s, 9H).

Reference Example 15 Synthesis of tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate

To a mixed solution of tetrahydrofuran (12 mL) and water (3 mL) containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (1.5 g, 3.5 mmol), sodium periodate (2.3 g, 10.5 mmol) and osmium tetraoxide (2.5 w/v % in tert-butanol, 1.8 mL, 0.15 mmol) were added with ice-cooling. After the reaction mixture was stirred at room temperature for 5 hr, aqueous sodium sulfite was added here, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine, and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off, and the residue was purified with column chromatography (20% ethyl acetate-hexane) to obtain the title compound (895 mg, 2.08 mmol, yield 59%).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 9.44 (s, 1H), 8.19 (s, 1H), 7.14 (dt, J=9.8 and 2.9 Hz, 2H), 6.81 (d, J=6.8 Hz, 2H), 6.73 (d, J=2.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.84 (d, J=37.3 Hz, 1H), 1.56 (s, 2H), 1.38 (t, J=7.1 Hz, 3H).

Reference Example 16 Synthesis of {7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyrimidin-6-yl}acetic acid

To a mixed solution of water (0.5 mL) and tert-butanol (5 mL) containing tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (431 mg, 1.0 mmol), sodium dihydrogen phosphate (1.56 g, 10 mmol), 2-methyl-2-butene (1.1 mL, 10 mmol) and sodium chlorite (181 mg, 2.0 mmol) were added, and this mixture was stirred at room temperature for 4 hr. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (468 mg).

Reference Example 17 Synthesis of tert-butyl [5-chloro-6-(3-oxopropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate

To a methylene chloride (1.7 mL) solution containing tert-butyl [5-chloro-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (155 mg, 0.346 mmol), Dess-Martin periodinane (152 mg, 0.381 mmol) was added with ice-cooling, and this mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified with column chromatography (10 to 20% ethyl acetate-hexane) to obtain the title compound (117 mg, yield 76%).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 9.68 (s, 1H), 8.16 (s, 1H), 7.15 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 6.69 (d, J=1.9 Hz, 1H), 3.98 (q, J=6.8 Hz, 2H), 3.03 (m, 2H), 2.69 (m, 1H), 1.97 (m, 1H), 1.39 (t, 3H), 1.26 (s, 9H).

Reference Example 18 Synthesis of tert-butyl {6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}(4-ethoxyphenyl)carbamate

To a 1,4-dioxane (13 mL) solution containing {6-[3-(tert-butyldimethylsilanyloxy)propyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}(4-ethoxyphenyl)amine (1.89 g, 4.12 mmol), were added triethylamine (861 μL, 6.18 mmol), di-tert-butyl dicarbonate (1.08 g, 4.84 mmol) and N,N-dimethylaminopyridine (50.3 mg, 0.412 mmol), and this mixture was stirred at room temperature for 2 hr. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (10% ethyl acetate-hexane) to obtain the title compound (2.03 g).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.13 (d, J=2.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 6.66 (d, J=2.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 2H), 3.62 (m, 2H), 2.77 (m, 2H), 1.74 (m, 1H), 1.48 (m, 1H), 1.38 (t, J=7.1 Hz, 3H), 1.26 (s, 9H), 0.91 (s, 9H), 0.064 (s, 6H).

Reference Example 19 Synthesis of tert-butyl [5-chloro-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate

To a tetrahydrofuran (23 mL) solution containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (3.0 g, 7.0 mmol), borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution, 5.6 mL, 23 mmol) was added over 30 min with ice-cooling. This mixture was stirred at room temperature for 2 hr and then again cooled on ice. Here, 1 mol/L aqueous sodium hydroxide (11.2 mL, 11.2 mmol) was added over 20 min, and hydrogen peroxide (30% aqueous solution, 0.81 mL, 8.4 mmol) was added. The resultant mixture was stirred for 1 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (20% ethyl acetate-hexane) to obtain the title compound (2.02 g, yield 65%).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.15 (s, 1H), 7.19 (d, J=8.3 Hz, 2H), 6.82 (d, J=8.3 Hz, 2H), 6.68 (d, J=2.2 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.64 (J=6.0 Hz, 2H), 2.79 (s, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.26 (s, 9H).

Reference Example 20 Synthesis of tert-butyl [5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate

To a mixed solution of tetrahydrofuran (12 mL) and water (3 mL) containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (1.5 g, 3.5 mmol), sodium periodate (2.3 g, 10.5 mmol) and osmium tetraoxide (2.5 w/v % in tert-butanol, 1.8 mL, 0.15 mmol) were added with ice-cooling. After this mixture was stirred at room temperature for 5 hr, aqueous sodium sulfite was added here. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate.

The above product was dissolved in methanol (6 mL) and sodium borohydride (0.14 g, 3.5 mmol) was added to this solution with ice-cooling. After the reaction mixture was stirred for 30 min, aqueous ammonium chloride was added here. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (15% ethyl acetate-hexane) to obtain the title compound (1.0 g).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.17 (s, 1H), 7.20 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.0 Hz, 2H), 6.70 (d, J=2.2 Hz, 1H), 3.99 (q, J=7.0 Hz, 2H), 3.80 (br, 1H), 3.58 (br, 1H), 3.00 (br, 2H), 1.61 (s, 9H), 1.39 (t, J=6.8 Hz, 3H).

Reference Example 21 Synthesis of tert-butyl [5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate

To a mixed solution of acetone (11 mL) and water (22 mL) containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (1.0 g, 2.33 mmol), N-methylmorpholine-N-oxide (327 mg, 2.79 mmol) and osmium tetraoxide (2.5 w/v % in tert-butanol, 1.46 mL, 0.116 mmol) were added with ice-cooling. The mixture was allowed to warm to room temperature and stirred for 16 hr. After the reaction, aqueous sodium sulfite was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (50% ethyl acetate-hexane) to obtain the title compound (947 mg).

Reference Example 22 Synthesis of tert-butyl {6-[3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}(4-ethoxyphenyl)carbamate

To a methylene chloride (3.6 mL) solution containing tert-butyl [5-chloro-6-(2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (500 mg, 1.08 mmol), triethylamine (300 μL, 2.16 mmol), tert-butylchlorodimethylsilane (195 mg, 1.30 mmol) and N,N-dimethylpyridine (13 mg, 0.108 mmol) were added. After the reaction mixture was stirred at room temperature for 5 hr, 1 mol/L hydrochloric acid was added here, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography to obtain the title compound (503 mg).

Reference Example 23 Synthesis of tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

A mixture of tert-butyl [5-chloro-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (300 mg) and (S)-3-amino-1-tert-butoxycarbonylpiperidine (900 mg) was stirred at 90° C. for 16 hr. To the reaction solution, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.

Reference Example 24 Synthesis of tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

To a tetrahydrofuran (1.3 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(3-tert-butyldimethylsiloxypropyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (13.3 mg), was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 26 μL), and the mixture was stirred at room temperature for 3 hr. After the reaction, the mixture was purified with PTLC (50% ethyl acetate-hexane) to obtain the title compound (7.7 mg).

Reference Example 25 Synthesis of tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-methanesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

To a methylene chloride (2 mL) solution containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693 mmol), triethylamine (290 μL, 2.08 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added with ice-cooling, and the mixture was stirred for 30 min. After the reaction, 1 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.

Example 3 Synthesis of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

To a mixed solution of tetrahydrofuran (3 mL) and N,N-dimethylformamide (1 mL) containing tert-butyl (S)-3-[7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(2-methanesulfonyloxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (0.693 mmol), sodium hydride (with 40% mineral oil added) (55 mg) was added with ice-cooling, and the mixture was stirred for 2 hr. After the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.

HPLC retention time (HPLC condition A): 15.92 min

ESI/MS: 579.20 (M+H, C₃₁H₄₂N₆O₅)

Reference Example 26 Synthesis of tert-butyl (S)-3-(2-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyrimidin-6-yl}acetylamino)piperidine-1-carboxylate

To an N,N-dimethylformamide (0.5 mL) solution containing {7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyrimidin-6-yl}acetic acid (10.3 mg, 0.023 mmol) and (S)-3-amino-1-tert-butoxycarbonylpiperidine (9.2 mg, 0.046 mmol), diisopropylamine (50 μL) and O-(7-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (13.1 mg, 0.0345 mmol) were added, and the mixture was stirred at room temperature for 16 hr. To the reaction solution, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off, and the residue was purified with PTLC (50% ethyl acetate-hexane) to obtain the title compound (10.8 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.16 (s, 1H), 7.22 (t, J=6.3 Hz, 2H), 6.92 (d, J=7.8 Hz, 2H), 6.69 (d, J=2.0 Hz, 1H), 3.97 (q, J=5.5 Hz, 2H), 3.92 (m, 1H), 3.57-3.07 (m, 6H), 2.47-2.31 (m, 1H), 1.81 (m, 1H), 1.62 (s, 9H), 1.47 (s, 9H), 1.26 (t, J=6.2 Hz, 3H).

Example 4 Synthesis of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-oxo-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

To a mixed solution of tetrahydrofuran (0.3 mL) and N,N-dimethylformamide (0.1 mL) containing tert-butyl (S)-3-(2-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-5-chloropyrazolo[1,5-a]pyrimidin-6-yl}acetylamino)piperidine-1-carboxylate (4.3 mg), sodium hydride (with 40% mineral oil added) (10 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction solution, aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound.

Reference Example 27 Synthesis of tert-butyl (S)-3-(allyl-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-yl}amino)piperidine-1-carboxylate

To a mixed solution of tetrahydrofuran (0.6 mL) and N,N-dimethylformamide containing tert-butyl (S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (100 mg, 0.168 mmol), sodium hydride and allyl bromide were added at 0° C., and the mixture was stirred at 70° C. for 5 hr. To the reaction solution, water was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off to obtain the title compound (102 mg).

Example 5 Synthesis of tert-butyl (S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate

To a toluene (0.7 mL) solution containing tert-butyl (S)-3-(allyl-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-yl}amino)piperidine-1-carboxylate (28.5 mg, 0.035 mmol), Grubbs catalyst (8.4 mg, 0.0103 mmol) was added. After the mixture was stirred at 40° C. for 16 hr, the solvent was distilled off, and the residue was purified with PTLC (30% ethyl acetate-hexane) to obtain the title compound (10 mg).

Example 6 Synthesis of tert-butyl (S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7,8,9-tetrahydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate

tert-Butyl (S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate (12.5 mg) was hydrogenated in the presence of palladium-carbon (15 mg) in ethanol (1.2 mL) under a hydrogen atmosphere. After the reaction, the palladium-carbon was filtered off, and the filtrate was concentrated. The residue was used for the subsequent reaction without purification.

Example 7 Synthesis of tert-butyl (4-ethoxyphenyl)(5-hydroxy-6,7-dichloro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)carbamate

To a methanol (30 mL) solution containing tert-butyl [5-chloro-6-(2-oxoethyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (1.0 g, 2.3 mmol) and hydroxylamine hydrochloride (0.81 g, 11.6 mmol), sodium cyanoborohydride (0.73 g, 11.6 mmol) was added, and the mixture was heated at 50° C. for 16 hr. To the reaction solution, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, and the solvent was distilled off to obtain the title compound.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.85 (d, J=2.0 Hz, 1H), 7.19 (dd, J=2.2 and 6.8 Hz, 2H), 6.80 (dd, J=2.2 and 6.6 Hz, 2H), 6.26 (d, 1H), 3.97 (q, J=7.1 Hz, 2H), 3.79 (t, J=7.6 Hz, 2H), 2.71 (br, 2H), 1.37 (s, 9H), 1.26 (t, J=7.1 Hz, 3H).

Example 8 Synthesis of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

To a mixed solution of tetrahydrofuran (3.2 mL) and water (0.8 mL) containing tert-butyl (S)-3-{6-allyl-7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (375 mg, 0.632 mmol), sodium periodate (405 mg, 1.89 mmol) and osmium tetraoxide (2.5 w/v % tert-butanol solution, 793 μL, 0.063 mmol) were added, and the mixture was stirred. After the reaction, aqueous sodium sulfite was added to the solution, and the mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, and the solvent was distilled off to obtain the title compound.

Example 9 Synthesis of tert-butyl (S)-3-[8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-(tert-butyldimethylsilanyloxymethyl)-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate

To a methylene chloride (1 mL) solution containing tert-butyl (S)-3-{7-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6-[3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl]pyrazolo[1,5-a]pyrimidin-5-ylamino}piperidine-1-carboxylate (28.6 mg, 0.0495 mmol), Dess-Martin periodinane (25.2 mg, 0.0594 mmol) was added at 0° C., and the mixture was allowed to warm to room temperature and stirred for 3 hr. After the reaction, the reaction solution was concentrated, and the residue was purified with PTLC (30% ethyl acetate-hexane) to obtain the title compound (14.5 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.05 (d, J=2.2 Hz, 1H), 7.26 (dt, J=9.8 and 2.8 Hz, 2H), 6.74 (dt, J=9.8 and 2.8 Hz, 2H), 6.40 (d, J=2.2 Hz, 1H), 6.04 (s, 1H), 4.66 (d, J=12.9 Hz, 1H), 4.58 (d, J=13.4 Hz, 1H), 4.19-4.02 (m, 2H), 3.90 (q, J=7.0 Hz, 2H), 2.84 (br, 2H), 1.91 (m, 1H), 1.80 (m, 1H), 1.38 (s, 9H), 1.30 (t, J=7.1 Hz, 3H), 1.28 (s, 9H), 0.83 (s, J=13.0 Hz, 9H), 0.02 (d, J=16.8 Hz, 6H).

Reference Example 28 Synthesis of tert-butyl (S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

By using tert-butyl {6-[3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl]-5-chloropyrazolo[1,5-a]pyrimidin-7-yl}(4-ethoxyphenyl)carbamate, the title compound was synthesized by the same method as Reference example 7.

Reference Example 29 Synthesis of tert-butyl (S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldimethylsilanyloxy)-2-methanesulfonyloxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate

By using tert-butyl (S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldimethylsilanyloxy)-2-hydroxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate, the title compound was synthesized by the same method as Reference example 25.

Example 10 Synthesis of tert-butyl (S)-3-[8-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-(tert-butyldimethylsilanyloxymethyl)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate

By using tert-butyl (S)-3-[7-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-{3-(tert-butyldimethylsilanyloxy)-2-methanesulfonyloxypropyl}pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 1.

Example 11 Synthesis of (S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-008)

To a methylene chloride (4 mL) solution containing tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (0.693 mmol), trifluoroacetic acid (2 mL) was added with ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 16 hr. After the reaction, the reaction solution was poured into aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with PTLC {10% (2 mol/L ammonia/methanol)-methylene chloride} to obtain the title compound (97.0 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.74 (d, J=2.2 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.06 (d, J=2.2 Hz, 1H), 4.05 (t, J=7.1 Hz, 2H), 3.43 (m, 2H), 3.13 (m, 1H), 3.03 (m, 1H), 2.67 (t, 1H), 2.54 (m, 1H), 2.30 (t, 2H), 1.79 (m, 3H), 1.60 (m, 1H), 1.44 (t, 3H).

HPLC retention time (HPLC condition A): 7.30 min

ESI/MS: 379.15 (M+H, C₂₁H₂₆N₆O)

Example 12 Synthesis of (S)-(4-ethoxyphenyl)(5-piperidin-3-yl-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: F-001)

By using tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 8.30 (br, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.35 (dd, J=2.2 and 6.6 Hz, 2H), 6.99 (dd, J=2.2 and 6.6 Hz, 2H), 6.82 (d, J=3.9 Hz, 1H), 6.31 (d, J=2.2 Hz, 1H), 5.42 (d, J=3.9 Hz, 1H), 4.70 (m, 1H), 4.10 (q, J=7.1 Hz, 2H), 3.33 (m, 1H), 3.10 (m, 1H), 2.80 (m, 1H), 2.68 (m, 1H), 2.13-1.67 (m, 4H), 1.47 (t, J=7.1 Hz, 3H).

HPLC retention time: 7.91 min

ESI/MS: 377.14 (M+H, C₂₁H₂₄N₆O)

Example 13 Synthesis of (S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,9-dihydro-5H-1,4,5,10a-tetraazacyclohepta[f]inden-10-yl)amine (Compound No.: G-001)

By using tert-butyl (S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.81 (d, J=2.2 Hz, 1H), 7.54 (s, 1H), 7.02 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.16 (d, J=2.2 Hz, 1H), 5.71 (m, 2H), 4.47 (m, 1H), 4.02 (q, J=6.8 Hz, 2H), 3.82 (m, 2H), 3.31 (m, 1H), 3.05 (m, 1H), 2.98 (d, J=5.6 Hz, 2H), 2.74 (t, J=11.2 Hz, 1H), 2.55 (m, 1H), 2.02 (m, 1H), 1.96 (m, 2H), 1.67 (m, 2H), 1.42 (t, J=6.8 Hz, 3H).

HPLC retention time (HPLC condition A): 9.17 min

ESI/MS: 405.04 (M+H, C₂₃H₂₈N₆O₁)

Example 14 Synthesis of (S)-(4-ethoxyphenyl)(5-piperidin-3-yl-6,7,8,9-tetrahydro-5H-1,4,5,10a-tetraazacyclohepta[f]inden-10-yl)amine (Compound No.: C-001)

By using tert-butyl (S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7,8,9-tetrahydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.76 (d, J=2.2 Hz, 1H), 7.50 (s, 1H), 7.03 (d, J=8.8 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 6.06 (d, J=2.2 Hz, 1H), 4.59 (m, 1H), 4.03 (q, J=7.1 Hz, 2H), 3.38 (m, 2H), 3.26 (m, 1H), 3.10 (m, 1H), 2.82 (m, 1H), 2.66 (t, J=11.0 Hz, 1H), 2.56 (m, 1H), 2.17 (m, 3H), 2.00 (m, 1H), 1.82-1.66 (m, 5H), 1.42 (t, J=7.1 Hz, 3H).

HPLC retention time: 8.59 min

ESI/MS: 407.12 (M+H, C₂₃H₃₀N₆O₁)

Example 15 Synthesis of 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol (Compound No.: A-020)

By using tert-butyl (4-ethoxyphenyl)(5-hydroxy-6,7-dichloro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)carbamate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.84 (d, J=2.2 Hz, 1H), 7.82 (s, 1H), 7.16 (dd, J=2.2 and 6.6 Hz, 2H), 6.90 (dd, J=2.2 and 6.6 Hz), 6.26 (d, J=2.2 Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.53 (t, J=7.6 Hz, 2H), 2.23 (t, J=7.6 Hz, 2H), 1.44 (t, J=7.1 Hz, 3H).

HPLC retention time (HPLC condition A): 7.74 min

ESI/MS: 312.15 (M+H, C₁₆H₁₇N₅O₂)

Example 16 Synthesis of 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl acetate (Compound No.: A-021)

To a methylene chloride (0.5 mL) solution containing 8-(4-ethoxyphenylamino)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-ol (2.8 mg), triethylamine (50 μL) and acetic anhydride (50 μL) were added. After this solution was stirred at room temperature for 30 min, the solvent was concentrated, and the residue was purified with PTLC (70% ethyl acetate-hexane) to obtain the title compound (2.3 mg).

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.93 (s, 1H), 7.90 (d, 2H), 7.19 (dd, J=2.2 and 6.6 Hz, 2H), 6.91 (dd, J=2.2 and 6.6 Hz, 2H), 6.35 (d, 1H), 4.06 (q, J=6.8 Hz, 2H), 3.58 (t, J=7.6 Hz, 2H), 2.36 (t, J=7.3 Hz, 2H), 2.57 (s, 3H), 1.45 (t, J=7.1 Hz, 3H).

HPLC retention time (HPLC condition A): 10.8 min

ESI/MS: 354.06 (M+H, C₁₈H₁₉N₅O₃)

Example 17 Synthesis of [5-(4-aminocyclohexyl)-5,6,7,8-tetrahydro-1,4,5,9a-tetraazacyclopenta[b]naphthalen-9-yl](4-ethoxyphenyl)amine (Compound No.: B-002)

By using tert-butyl [5-(4-tert-butoxycarbonylaminocyclohexyl)-5,6,7,8-tetrahydro-1,4,5,9a-tetraazacyclopenta[b]naphthalen-9-yl](4-ethoxyphenyl)carbamate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 7.75 (d, J=2.2 Hz, 1H), 7.46 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.03 (d, J=2.2 Hz, 1H), 4.95 (m, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.21 (t, J=5.6 Hz, 2H), 2.76 (m, 1H), 2.10 (t, J=6.1 Hz, 2H), 2.00 (m, 2H), 1.78 (m, 4H), 1.53 (m, 2H), 1.42 (t, J=6.8 Hz, 3H).

HPLC retention time (HPLC condition A): 7.2 min

ESI/MS: 407.34 (M+H, C₂₃H₃₀N₆O)

Example 18 Synthesis of (S)-(2-methylbenzothiazol-6-yl)(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-022

By using tert-butyl (S)-3-(8-{tert-butoxycarbonyl-[4-(2-methylbenzothiazol-6-yl)]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 10.63 (s, 2H), 9.71 (s, 1H), 8.49 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.89 (d, J=2.2 Hz, 2H), 7.82 (d, J=2.2 Hz, 2H), 7.41 (dd, J=8.5 and 2.2 Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 4.68 (t, J=11.3 Hz, 1H), 3.72 (dq, J=31.1 and 9.0 Hz, 2H), 3.48-3.34 (m, 3H), 3.01 (m, 1H), 2.99 (s, 3H), 2.39 (t, J=8.5 Hz, 2H), 2.08-1.79 (m, 4H).

HPLC retention time (HPLC condition A): 6.19 min

ESI/MS: 406.10 (M+H, C₂₁H₂₃N₇S)

Example 19 Synthesis of (S)-[4-(2-methoxyethoxy)phenyl](5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-023)

By using tert-butyl (S)-3-(8-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

¹H NMR (CDCl₃, 400 MHz) δ(ppm): 10.93 (s, 1H), 9.65 (s, 1H), 8.29 (s, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.26 (d, J=7.8 Hz, 2H), 7.00 (dd, J=9.6 and 2.8 Hz, 2H), 6.39 (d, J=2.0 Hz, 1H), 4.67 (t, J=11.8 Hz, 1H), 4.17 (t, J=4.5 Hz, 2H), 3.80 (dd, J=5.4 and 3.7 Hz, 2H), 3.71 (dq, J=28.4 and 6.8 Hz, 2H), 3.48 (s, 3H), 3.48-3.30 (m, 3H), 3.04 (m, 1H), 2.37 (t, 2H, J=8.5 Hz), 2.08-1.79 (m, 4H).

HPLC retention time (HPLC condition A): 6.19 min

ESI/MS: 409.15 (M+H, C₂₂H₂₈N₆O₂)

Example 20 Synthesis of (S)-(4-ethoxyphenyl)(3-fluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-018) and (S)-(2,3-difluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)(4-ethoxyphenyl)amine (Compound No.: A-019)

To an N,N-dimethylformamide (1.3 mL) solution containing tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (78 mg, 0.14 mmol), an N,N-dimethylformamide (1.4 mL) solution containing 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (38.3 mg, 0.108 mmol) was added with ice-cooling, and this mixture was stirred at room temperature for 4 days. After the reaction, 0.2 mol/L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off. To the residue, methylene chloride (3.0 mL) and trifluoroacetic acid (0.3 mL) were added, and this solution was stirred at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified with preparative HPLC to obtain the title compounds.

-   (S)-(4-Ethoxyphenyl)(3-fluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine     (Compound No.: A-018)

Yield: 7.6 mg

HPLC retention time (HPLC condition A): 8.50 min

ESI/MS: 397.08 (M+H, C₂₁H₂₅FN₆O)

-   (S)-(2,3-Difluoro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)(4-ethoxyphenyl)amine     (Compound No.: A-019)

Yield: 14.9 mg

HPLC retention time (HPLC condition A): 10.23 min

ESI/MS: 415.07 (M+H, C₂₁H₂₄F₂N₆O₁)

Example 21 Synthesis of (S)-{8-(4-ethoxyphenylamino)-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-6-yl}methanol (Compound No.: A-024)

By using tert-butyl (S)-3-[8-{tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6-(tert-butyldimethylsilanyloxymethyl)-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate, the title compound was synthesized by the same method as Example 11.

HPLC retention time (HPLC condition A): 6.41 min

ESI/MS: 409.10 (M+H, C₂₂H₂₈N₆O₂)

Example 22 Synthesis of tert-butyl (S)-3-{3-chloro-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

To a THF solution (2.0 mL) of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (12.5 mg, 0.0216 mmol), N-chlorosuccinimide (15.3 mg, 0.114 mmol) was added at room temperature and the mixture was stirred at room temperature for 1 hr. After the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was evaporated to obtain the title compound.

HPLC retention time (HPLC condition A): 16.69 min

ESI/MS: 613.10 (M+H, C₃₁H₄₁ClN₆O₅)

Example 23 Synthesis of tert-butyl (S)-3-{3-bromo-8-tert-butoxycarbonyl-(4-ethoxyphenyl)amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate

To a THF solution (2.0 mL) of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (20.0 mg, 0.0346 mmol), N-bromosuccinimide (31.4 mg, 0.176 mmol) was added on ice-bath cooling and the mixture was stirred for 10 min. After the reaction, aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was evaporated and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (16.8 mg).

HPLC retention time (HPLC condition A): 16.79 min

ESI/MS: 657.05, 659.10 (M+H, C₃₁H₄₁BrN₆O₅)

Example 24 Synthesis of (S)-(4-ethoxyphenyl)-(3-chloro-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No. A-101)

The title compound was synthesized using tert-butyl (S)-3-{3-chloro-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate by the same method as Example 11.

HPLC retention time (HPLC condition A): 9.82 min

ESI/MS: 413.05 (M+H, C₂₁H₂₅ClN₆O₁)

Example 25 Synthesis of (S)-(4-ethoxyphenyl)-(3-bromo-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-102)

The title compound was synthesized using tert-butyl (S)-3-{3-bromo-8-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate by the same method as Example 11.

HPLC retention time (HPLC condition A): 10.04 min

ESI/MS: 456.95, 459.00 (M+H, C₂₁H₂₅BrN₆O₁)

Example 26 Synthesis of (S)-furan-2-yl-(5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-yl)amine (Compound No.: A-095) and (S)-5-piperidin-3-yl-6,7-dihydro-5H-1,4,5,8a-tetraaza-s-indacen-8-ylamine (Compound No.: A-092)

To a methylene chloride solution (2.0 mL) of tert-butyl (S)-3-{8-[tert-butoxycarbonyl-furan-2-ylmethylamino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (60.0 mg, 0.111 mmol), trifluoroacetic acid (1.0 mL) was added on ice-bath cooling and the mixture was allowed to warm up to room temperature and stirred for 4 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified with preparative HPLC to obtain the two title compounds.

(Compound No.: A-095)

Yield: 18.0 mg

HPLC retention time (HPLC condition A): 5.40 min

ESI/MS: 338.95 (M+H, C₁₈H₂₂N₆O₁)

(Compound No.: A-092)

Yield: 13.4 mg

HPLC retention time (HPLC condition B): 2.51 min

ESI/MS: 259.00 (M+H, C₁₃H₁₈N₆O₁)

Example 27 Synthesis of tert-butyl (S)-3-(3-iodo-8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl)piperidine-1-carboxylate

To a THF solution (1.5 mL) of tert-butyl (S)-3-(8-[tert-butoxycarbonyl-{4-(2-methoxyethoxy)phenyl}amino]-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl}piperidine-1-carboxylate (110.6 mg, 0.182 mmol), N-iodosuccinimide (49.1 mg, 0.218 mmol) was added at room temperature and the mixture was stirred for 3 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (118.9 mg).

HPLC retention time (HPLC condition A): 16.48 min

ESI/MS: 735.24 (M+H, C₃₂H₄₃IN₆O₆)

Example 28 Synthesis of tert-butyl (S)-3-[3-iodo-8-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate

To a THF solution (1.5 mL) of tert-butyl (S)-3-[8-{tert-butoxycarbonyl-(2-methylbenzothiazol-6-yl)amino}-6,7-dihydro-1,4,5,8a-tetraaza-s-indacen-5-yl]piperidine-1-carboxylate (97.6 mg, 0.161 mmol), N-iodosuccinimide (43.5 mg, 0.193 mmol) was added at room temperature and the mixture was stirred for 3 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was removed under reduced pressure and the residue was purified with column chromatography (30% ethyl acetate-hexane) to obtain the title compound (109.7 mg).

HPLC retention time (HPLC condition A): 16.68 min

ESI/MS: 732.18 (M+H, C₃₁H₃₈₁N₇O₄S)

Example 29

The compounds listed in the following Table H were synthesized from the corresponding starting material and reagent according to each method described in Examples 11 to 21, and 24 to 26. The compound number assigned to each compound in Table H corresponds to the compound number of the example listed in the above Tables A to G. The structures of novel compounds isolated were confirmed by ¹H NMR and/or mass analysis on a single quadrupole instrumentation equipped with an electrospray source or other appropriate analytical methods.

For results of mass analysis, M+H, that is, the measured value observed as the molecular mass of compound (M) with one proton (H) added, is shown. “HPLC retention time” represents the retention time (unit: min) of compound in HPLC analysis under the above-mentioned analytical conditions. “Conditions for HPLC” represents the conditions for HPLC analysis on that occasion.

TABLE H HPLC Retention Compound ESI/MS Time Conditions NO. M + H (min) for HPLC A-001 379.30 7.22 A A-002 393.18 6.75 A A-003 393.18 6.78 A A-004 393.18 7.20 A A-005 339.16 6.44 A A-006 353.18 6.25 A A-007 381.17 8.60 A A-009 379.22 6.42 A A-010 455.22 8.27 A A-011 393.25 7.82 A A-012 393.20 7.95 A A-013 365.20 6.87 A A-014 393.12 6.74 A A-015 393.12 7.84 A A-016 379.09 7.78 A A-017 386.10 11.25 A A-025 349.15 6.13 A A-026 329.20 6.89 A A-027 327.20 5.69 B A-032 335.05 6.03 A A-058 375.10 5.02 A A-091 443.10 5.84 A A-096 273.10 1.55 B A-099 393.05 6.65 A A-100 391.00 9.28 A B-001 393.12 8.81 A B-003 407.28 9.12 A B-004 366.30 11.14 A B-005 380.32 11.74 A B-006 394.29 10.24 A B-007 381.30 8.56 A B-009 368.31 9.66 A B-010 382.27 10.18 A B-011 350.32 9.72 A B-012 378.31 11.13 A B-013 407.28 7.72 A B-014 393.31 7.84 A B-015 367.27 6.77 A B-016 469.32 11.31 A B-017 393.31 6.91 A B-018 401.30 8.77 A B-019 401.24 7.86 A B-020 401.17 8.64 A B-021 379.00 7.88 A B-022 407.06 9.10 A D-001 393.15 6.94 A D-002 407.08 7.78 A D-003 353.11 7.22 A D-004 393.12 7.97 A D-005 407.15 8.16 A D-006 407.08 8.36 A D-007 469.06 10.19 A E-001 407.12 8.84 A F-002 407.25 8.08 A

Example 30 General Measurement Method for Determining Inhibition of MAPKAP-K2 Enzyme Activity (Preparation of Solutions of Compounds)

Each compound was dissolved to DMSO to prepare a solution with a concentration of 20 mmol/L and this solution was stored at −20° C. This stock solution was diluted with DMSO successively to prepare solutions with 200-fold concentrations of a necessary range. These solutions were further diluted with water at a ratio of 1:20 to prepare solutions with 10-fold concentrations of a necessary range. Each of these solutions (5 μL) was used for each reaction in 50 μL-scale. Through the dilution series of all compounds, the final DMSO concentration was kept at 0.5%. Conventional tests for the compounds were carried out at a final concentration ranging from 100 μmol/L to 0.03 μmol/L, but in some cases, tests were carried out at lower concentrations, depending on activity.

(Measurements of MAPKAP-K2 Enzyme Activity)

To a DMSO solution (5 μL) containing a test compound at 5%, a solution (25 μL) containing a peptide substrate [peptide substrate 60 μmol/L, ATP 20 μmol/L, Tris buffer 60 mmol/L (pH 7.5), EGTA 0.2 mmol/L, β-mercaptoethanol 0.2%, magnesium acetate 20 mmol/L, [γ-33P]ATP 0.1 μCi (specific radioactivity ca. 110 TBq/mmol)] was added. The reaction was initiated by further adding a solution (20 μL) containing MAPKAP-K2 enzyme [recombinant human MAPKAP-K210 mU, Tris buffer 50 mmol/L (pH 7.5), EGTA 0.1 mmol/L, β-mercaptoethanol 0.1%, BSA 0.1%]. After the reaction was carried out at room temperature for 30 min, 200 mmol/L phosphoric acid (50 μL) was added to quench the reaction, and 90 μL of the reaction mixture was adsorbed on a multiscreen PH plate (Millipore). The plate was washed with 100 mmol/L phosphoric acid. After the plate was dried, 30 μL of MicroScint™-O (Perkin-Elmer) was added here, and the radioactivity (cpm) was measured on a scintillation counter to determine the inhibitory activity. The peptide substrate was Lys-Lys-Leu-Asn-Arg-Thr-Leu-Ser-Val-Ala.

(Note)

% Reference=(X−B)/(Tot−B)×100

% Inhibition=100%−% Reference

X=count per minute of the well with a test compound B=count per minute of the well without the enzyme Tot=count per minute of the well with only DMSO solvent and without a test compound

(Calculation of MAPKAP-K2 Inhibitory Activity)

IC50 value=a concentration of compound at which 50% inhibition is observed The efficacy of each compound in Tables A to G against MAPKAP-K2 is listed in the following Table J. (For activity strength in the table, +++represents IC50 value <10 μmol/L, ++represents 10 μmol/L≦IC50 value <50 μmol/L and +represents 50 μmol/L≦IC50 value <100 μmol/L.)

TABLE J Compound No. Activity strength A-001 +++ A-002 +++ A-003 ++ A-004 + A-005 +++ A-006 +++ A-007 + A-008 +++ A-009 +++ A-010 ++ A-012 ++ A-013 +++ A-014 + A-018 +++ A-019 ++ A-020 +++ A-022 +++ A-023 +++ A-024 +++ A-025 +++ A-026 +++ A-027 +++ A-032 +++ A-058 +++ A-091 +++ A-092 +++ A-095 +++ A-096 +++ A-099 +++ A-100 +++ B-001 +++ B-002 +++ B-003 ++ B-007 + B-013 + B-014 +++ B-015 ++ B-016 ++ B-017 +++ B-018 + B-021 +++ B-022 ++ C-001 +++ D-001 ++ D-002 + D-003 + D-006 ++ F-001 +++ F-002 ++ G-001 +++

FIELD OF INDUSTRIAL APPLICATION

The compounds of the present invention are useful as MAPKAP-K2 inhibitors. Further, by using the compounds of the present invention as active ingredients, there is provided a therapeutic agent for neurodegenerative and/or neurological disorders (including dementia), inflammatory disease, sepsis, autoimmune diseases, destructive osteopathy, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma and/or chronic obstructive pulmonary disease (COPD). 

1. A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1):

[wherein, R¹ represents a hydrogen atom or a halogen; R² represents a hydrogen atom or a halogen; R³ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR⁵; R⁵ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R⁶; R⁶ represents an optionally substituted C1-C8 alkyl group; n represents 0 or 1, or n represents 0 when R³ is —OR⁵; R⁴ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted heterocyclylalkyl group or an optionally substituted C7-C16 aralkyl group; the substituents in the optionally substituted C6-C14 aryl group as R⁴ are one or more substituents selected from the group consisting of halogen, —CN, —NO₂, —CHO, —OH, —COOH, optionally substituted C1-C8 alkyl group, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)—R¹³³, —O—C(═O)R²⁶, —C(═O)OR²⁷, —NR²⁸C(═O)R²⁹, —NR³⁰R³¹, —C(═O)NR³²R³³, —NR³⁴C(═X¹)OR³⁵, —NR³⁶C(═X²)NR³⁷R³⁸, —NR³⁹—SO₂R⁴⁰, —S(O)_(r)—R⁴¹ and —SO₂NR⁴²R⁴³, wherein X¹ or X² represents O, S, N—CN or NH and r represents 0 to 2; W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group, and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group, —NR¹⁵⁰R¹⁵¹ or an optionally substituted phenoxy group and in this case m represents 1 to 4; R²⁶ to R⁴³, R¹³³, R¹⁵⁰ and R¹⁵¹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C2-C8 alkenyl, an optionally substituted C2-C8 alkynyl, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group, an optionally substituted aralkyl group or an optionally substituted heterocyclylalkyl group, or, when R³⁰ and R³¹R³² and R³³R³⁷ and R³⁸, R⁴² and R⁴³ or R¹⁵⁰ and R¹⁵¹ are optionally substituted alkyl groups, the substituents in each combination may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; -A-B- represents —CH₂—CH(-Z¹)-, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂—, —CH═C(-Z²)— or —(CH₂)_(q)—C(═O)—; p represents 3 or 4 and q represents 1 or 2; Z¹ and Z² may be identical or different and each represents a hydrogen atom or —CH₂—OR¹¹; and R¹¹ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or a substituted silyl group.]
 2. A pyrazolopyrimidine derivative or medically acceptable salt thereof represented by formula (1):

[wherein, R¹ represents a hydrogen atom or a halogen; R² represents a hydrogen atom or a halogen; R³ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted heterocyclic group, an optionally substituted C6-C14 aryl group or —OR⁵; R⁵ represents a hydrogen atom, an optionally substituted C1-C8 alkyl group or —(C═O)R⁶; R⁶ represents an optionally substituted C1-C8 alkyl group; n represents 0 or 1 or n represents 0 and when R³ is —OR⁵; R⁴ represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted C7-C16 aralkyl group; the substituents in the optionally substituted C6-C14 aryl group as R⁴ are one or more substituents selected from the group consisting of halogen, —CN, —NO₂, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR⁷, —NR⁸C(═O)R⁹, —NR¹⁰R¹²⁷, —C(═O)NR¹²⁸R¹²⁹ and —SO₂NR¹³⁰R¹³¹; W represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group or an optionally substituted heterocyclic group and in this case m represents 0 to 4; or W represents an optionally substituted C1-C8 alkoxy group or an optionally substituted phenoxy group and in this case m represents 1 to 4; R⁷ to R¹⁰ and R¹²⁷ to R¹³¹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group, or, when R¹⁰ and R¹²⁷, R¹²⁸ and R¹²⁹ or R¹³⁰ and R¹³¹ are optionally substituted alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which these substituents bond; -A-B- represents —CH₂—CH(-Z³)-, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂—, —CH═C(-Z⁴)— or —(CH₂)_(q)—C(═O)—; p represents 3 or 4 and q represents 1 or 2; Z³ and Z⁴ may be identical or different and each represents a hydrogen atom or —CH₂—OR¹¹; and R¹¹ represents a hydrogen atom or an optionally substituted C1-C8 alkyl group.]
 3. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R¹ is a hydrogen atom.
 4. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R² is a hydrogen atom.
 5. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R² is a halogen.
 6. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted heterocyclic group.
 7. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R³ is an unsubstituted C1-C4 alkyl group, a substituted C1-C4 alkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, phenyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, —CN, —CHO, —OH, —(C═O)OH, —(C═O)OR⁸⁶—(C═O)NR⁸⁷R⁸⁸ and —NR⁸⁹R⁹⁰; R⁸⁶ represents a C1-C4 alkyl group, a C3-C8 cycloalkyl group or a phenyl group; R⁸⁷ and R⁸⁸ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or an aralkyl group; R⁸⁹ represents a hydrogen atom, a C1-C4 alkyl group, a phenyl group or a benzyl group; R⁹⁰ represents a hydrogen atom, a C1-C4 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, or, when R⁸⁹ and R⁹⁰ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond; further this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which R⁸⁹ and R⁹⁰ bond), an unsubstituted C3-C8 cycloalkyl group, a substituted C3-C8 cycloalkyl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —OH, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkoxy group and —NR⁹¹R⁹², wherein R⁹¹ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R⁹² represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group), an unsubstituted heterocyclic group or a substituted heterocyclic group (wherein, when carbon atom(s) in the substituted heterocyclic group are substituted, the substituent(s) are 1 to 3 substituents selected from the group consisting of halogen, —(C═O)OH, C1-C4 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, phenyl group, benzyl group, C1-C4 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens and —NR⁹³R⁹⁴, wherein R⁹³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group and R⁹⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, wherein, when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group).
 8. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R³ is an unsubstituted heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted saturated heterocyclic group (wherein the heterocyclic group represents a monocyclic 5- to 8-membered heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in the heterocycle and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group and tert-butoxycarbonyl group), a C1-C4 alkyl group substituted with one amino group or a C3-C8 cycloalkyl group substituted with one amino group.
 9. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R³ is a piperidyl group, a pyrrolidinyl group or a cyclohexyl group substituted with an amino group.
 10. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein n is
 0. 11. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group.
 12. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W, optionally substituted C6-C14 aryl group, optionally substituted heterocyclic group, —C(═O)OR⁷ and —C(═O)NR⁹R¹⁰.
 13. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group and —O—(CH₂)_(m)—W.
 14. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more —O—(CH₂)_(m)—W, wherein W is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted heterocyclic group or an optionally substituted C1-C8 alkoxy group.
 15. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, optionally substituted C6-C14 aryl group and optionally substituted heterocyclic group.
 16. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group and the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —C(═O)OR⁷ and —C(═O)NR⁹R¹⁰.
 17. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C8 alkyl group, —O—(CH₂)_(m)—W and —C(═O)OR¹¹³, wherein W represents a hydrogen atom, an optionally substituted C1-C4 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted monocyclic or bicyclic heterocyclic group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4, and R¹¹³ represents an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted phenyl group).
 18. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted phenyl group (wherein the substituent is one —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m represents 0 to 4; or W represents an optionally substituted C1-C4 alkoxy group and m represents 1 to 4).
 19. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, optionally substituted phenyl group and optionally substituted monocyclic or bicyclic heterocyclic group).
 20. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted C6-C14 aryl group (wherein the substituents are one or more substituents selected from the group consisting of halogen, —CN, optionally substituted C1-C4 alkyl group, —C(═O)OR¹¹³ and —C(═O)NR¹¹⁸R¹¹⁹, wherein R¹¹³, R¹¹⁸ and R¹¹⁹ may be identical or different and each represents a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group or an optionally substituted C6-C14 aryl group; and when R¹¹⁸ and R¹¹⁹ are alkyl groups, they may form a saturated or unsaturated 5- to 7-membered ring together with the nitrogen atom to which they bond, and this ring may contain 1 or 2 heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom besides the nitrogen atom to which they bond).
 21. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted heterocyclic group.
 22. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein, when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, —CN, C1-C8 alkyl group, C1-C4 alkyl group substituted with 1 to 9 halogens, C1-C8 alkoxy group, C1-C4 alkoxy group substituted with 1 to 9 halogens, phenyl group, monocyclic or bicyclic heterocyclic group, —C(═O)OR¹²², —NR¹²³R¹²⁴ and —C(═O)NR¹²⁵R¹²⁶, wherein R¹²³ represents a hydrogen atom, a C1-C8 alkyl group, a phenyl group or a benzyl group, R¹²⁴ represents a hydrogen atom, a C1-C8 alkyl group, a benzyl group, an acetyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group, R¹²² represents a C1-C8 alkyl group, a C3-C8 cycloalkyl group or a phenyl group, and R¹²⁵ and R¹²⁶ may be identical or different and each represents a hydrogen atom, a C1-C8 alkyl group, a C3-C8 cycloalkyl group, a phenyl group or a benzyl group; when nitrogen atom(s) in the heterocycle are substituted, the substituents are one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group).
 23. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein the bicyclic heteroaryl group means a bicyclic heteroaryl group wherein a phenyl group is fused with an aromatic heterocycle containing 1 or 2 heteroatoms selected from the group consisting of N, O and S; when carbon atom(s) in the bicyclic heteroaryl group are substituted, the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens; when nitrogen atom(s) in the heterocycle are substituted, the substituent represents one or more C1-C4 alkyl group).
 24. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is a hydrogen atom, an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C7-C16 aralkyl group or an optionally substituted heterocyclylalkyl group.
 25. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein R⁴ is an optionally substituted heterocyclylalkyl group.
 26. The pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2, wherein -A-B- is —CH₂—CH₂—, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂— or —CH═CH—.
 27. A pyrazolopyrimidine derivative represented by formula (2):

[wherein, R¹, R², R³, R⁴, n and -A-B- are as defined in either claim 1 or 2, and Boc represents tert-butoxycarbonyl].
 28. The pyrazolopyrimidine derivative according to claim 27, wherein R¹ and R² are a hydrogen atom.
 29. The pyrazolopyrimidine derivative according to claim 27, wherein R¹ is a hydrogen atom and R² is a halogen.
 30. The pyrazolopyrimidine derivative according to claim 27, wherein R³ is an optionally substituted C1-C8 alkyl group, an optionally substituted cyclohexyl group or an optionally substituted heterocyclic group (wherein the heterocyclic group means a 3- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S).
 31. The pyrazolopyrimidine derivative according to claim 27, wherein R³ is an unsubstituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S), a substituted heterocyclic group (wherein the heterocyclic group means a 5- to 8-membered monocyclic heterocyclic group containing 1 or 2 heteroatoms selected from the group consisting of N, O and S, and the substituent bonds to a nitrogen atom in a saturated heterocyclic group and the substituents represent one or more substituents selected from the group consisting of C1-C4 alkyl group, benzyl group, acetyl group, tert-butoxycarbonyl group and benzyloxycarbonyl group), a C1-C4 alkyl group substituted with an amino group or a C3-C8 alkyl group substituted with an amino group.
 32. The pyrazolopyrimidine derivative according to claim 27, wherein R⁴ is an optionally substituted C1-C8 alkyl group, an optionally substituted C3-C8 cycloalkyl group, an optionally substituted C6-C14 aryl group, an optionally substituted heterocyclic group or an optionally substituted heterocyclylalkyl group.
 33. The pyrazolopyrimidine derivative according to claim 27, wherein R⁴ is an optionally substituted phenyl group or an optionally substituted bicyclic heteroaryl group.
 34. The pyrazolopyrimidine derivative according to claim 27, wherein R⁴ is an optionally substituted phenyl group (wherein the substituents are one or more —O—(CH₂)_(m)—W, wherein W represents a hydrogen atom or an optionally substituted C1-C4 alkyl group and m is 0 to 4, or W represents an optionally substituted C1-C4 alkoxy group and m is 2 to 4).
 35. The pyrazolopyrimidine derivative according to claim 27, wherein R⁴ is an optionally substituted bicyclic heteroaryl group (wherein the substituents are 1 to 3 substituents selected from the group consisting of halogen, C1-C4 alkyl group and C1-C4 alkyl group substituted with 1 to 9 halogens.).
 36. The pyrazolopyrimidine derivative according to claim 27, wherein -A-B- is —CH₂—CH₂—, —(CH₂)_(p)—, —CH₂—CH═CH—CH₂— or —CH═CH—.
 37. The pyrazolopyrimidine derivative according to claim 27, wherein n is
 0. 38. A pharmaceutical composition comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2 and a pharmaceutically acceptable carrier.
 39. A MAPKAP-K2 inhibitor comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2 as an active ingredient.
 40. A therapeutic agent comprising the pyrazolopyrimidine derivative or medically acceptable salt thereof according to claim 1 or 2 as an active ingredient for neurodegenerative and/or neurological disorders (including dementia), sepsis, autoimmune diseases, destructive osteopathy, inflammatory bowel disease, psoriasis, diabetes mellitus, cancer, ischemic reperfusion injury, angiodysplasia, cachexia, obesity, angiogenesis, asthma or chronic obstructive pulmonary disease (COPD).
 41. The therapeutic agent according to claim 40, wherein the autoimmune disease is rheumatoid arthritis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis, graft-versus-host disease, diabetes mellitus or Crohn's disease. 